WO2024017854A1 - Novel biomarkers for determining prostate cancer - Google Patents
Novel biomarkers for determining prostate cancer Download PDFInfo
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- WO2024017854A1 WO2024017854A1 PCT/EP2023/069843 EP2023069843W WO2024017854A1 WO 2024017854 A1 WO2024017854 A1 WO 2024017854A1 EP 2023069843 W EP2023069843 W EP 2023069843W WO 2024017854 A1 WO2024017854 A1 WO 2024017854A1
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57434—Specifically defined cancers of prostate
Definitions
- the present invention relates to a method of diagnosing prostate cancer in an individual. Further, the present invention relates to a method of determining lymph node involvement in an individual suffering from prostate cancer. Furthermore, the present invention relates to a method of determining the course of prostate cancer in an individual. The present invention also relates to a method of classifying prostate cancer in an individual. In addition, the present invention relates to a method of determining the risk for recurrence/relapse of prostate cancer in an individual. Moreover, the present invention relates to a kit useful to carry out these methods.
- the prostate is a small walnut shaped gland in the pelvis of men. It is located next to the bladder and can be examined by getting a digital rectal exam. Prostate cancer is a form of cancer that develops in the prostate gland. It is the second-leading cause of cancer deaths for men in the United States.
- prostate cancer Early diagnosis of prostate cancer often increases the likelihood of successful treatment or cure of such disease.
- the problem is that the majority of the prostate cancer patients are asymptomatic. Diagnosis in such cases is based on abnormalities detected by screening for serum levels of prostate-specific antigen (PSA) or findings on digital rectal examination (DRE).
- PSA prostate-specific antigen
- DRE digital rectal examination
- prostate cancer can be an incidental pathologic finding when tissue is removed during transurethral resection to manage obstructive symptoms from benign prostatic hyperplasia.
- patients may present with symptoms of primary or secondary/metastatic disease or due to the generalized effect of malignancy.
- Symptoms of the primary disease are, in some cases, attributable to those originating from the prostate volume rather than cancer symptoms per se. These symptoms usually include lower urinary tract symptoms (LUTS), urine retention, and/or hematuria. However, patients with benign prostatic hyperplasia alone can also have similar symptoms.
- LUTS lower urinary tract symptoms
- urine retention urine retention
- hematuria hematuria
- Symptoms of advanced disease result from any combination of lymphatic, hematogenous, or contiguous local spread. Skeletal manifestations are especially common with more than 70% of people who die of prostate carcinoma having metastatic disease in their bones.
- Prostate cancer has a strong capability of metastasizing to bone through the hematogenous route, and symptoms will depend on the site of metastasis with manifestation as localized bone pain.
- the most common bones involved include those of the axial skeleton such as spine and the pelvis, although any bone may be affected. Beside bones, liver and lungs can also be affected. Lymphatic spread results in lymph node metastasis.
- Advanced prostate cancer can also be associated with generalized symptoms of malignancy include lethargy, weight loss, and anemia, which may be secondary to marrow infiltration or destruction by metastasis.
- prostate cancer early and symptom-independent diagnosis of prostate cancer is highly desirable. As progression of prostate cancer is highly heterogeneous, there remains a need for correct prostate cancer classification which is a critical step in the management of the disease.
- the present inventors have identified new biomarkers which allow an improved diagnosis, monitoring, and classification of prostate cancer. They also allow determination of recurrent prostate cancer.
- the present invention relates to a method of diagnosing prostate cancer in an individual comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eIF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF).
- eIL4Gl eukaryotic Initiation Factor 4G1
- the present invention relates to a method of determining lymph node involvement in an individual suffering from prostate cancer comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2.
- eIF3D eukaryotic Initiation Factor 3D
- eIF3L eukaryotic Initiation Factor 3L
- eIF3M eIF3M
- eIF4B eIF5A
- eIF5B eukaryotic Elongation Factor 1A1
- eEFlAl eEFlAl
- eEFlB2 e
- the present invention relates to a method of determining the course of prostate cancer in an individual comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
- eIF3C eukaryotic Initiation Factor 3C
- eIF5A eukaryotic Initiation Factor 3A
- eIF3H eIF3H
- eIF5B ATP Binding Cassette Subfamily E Member 1
- the present invention relates to a method of classifying prostate cancer in an individual comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
- eIF3C eukaryotic Initiation Factor 3C
- eIF3H eukaryotic Initiation Factor 3C
- the present invention relates to a method of determining the risk for recurrence/relapse of prostate cancer in an individual comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
- eukaryotic Initiation Factor 4G1 eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
- eIF4Gl eukaryotic Initiation Factor 4G1
- MRRF Mitochondrial Ribosome Recycling Factor
- the present invention relates to the use of at least one biomarker for diagnosing prostate cancer, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eIF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF).
- eIL4Gl eukaryotic Initiation Factor 4G1
- the present invention relates to the use of at least one biomarker for determining lymph node involvement in an individual suffering from prostate cancer, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2.
- eukaryotic Initiation Factor 3D eukaryotic Initiation Factor 3D
- eIF3L eukaryotic Initiation Factor 3L
- eIF3M eIF3M
- eIF4B eIF5A
- eIF5B eukaryotic Elongation Factor 1A1
- eEFlAl eukaryotic Elongation Factor 1A1
- eEFlB2 eukaryotic E
- the present invention relates to the use of at least one biomarker for determining the course of prostate cancer in an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
- eIF3C eukaryotic Initiation Factor 3C
- eIF5A eukaryotic Initiation Factor 3A
- eIF3H eIF3H
- eIF5B ATP Binding Cassette Subfamily E Member 1
- the present invention relates to the use of at least one biomarker for classifying prostate cancer in an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
- eIF3C eukaryotic Initiation Factor 3C
- eIF3H eukaryotic Initiation Factor 3C
- eIF5A eIF5A
- eIF5B
- the present invention relates to the use of at least one biomarker for determining the risk for recurrence/relapse of prostate cancer in an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
- eukaryotic Initiation Factor 4G1 eIF4Gl
- MRRF Mitochondrial Ribosome Recycling Factor
- the present invention relates to a kit comprising means for determining the level of (i) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eIF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF),
- eEFID eukaryotic Elongation Factor ID
- eEFIG eEFIG
- eEF2 Mitochondrial Ribosome Recycling Factor
- At least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2,
- At least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1),
- At least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1), and/or
- At least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF), in a biological sample from an individual.
- eIF4Gl eukaryotic Initiation Factor 4G1
- MRRF Mitochondrial Ribosome Recycling Factor
- the terms used herein are defined as described in “A multilingual glossary of biotechnological terms: (IUPAC Recommendations)”, Leuenberger, H.G.W, Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
- IUPAC Recommendations Leuenberger, H.G.W, Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland.
- prostate cancer refers to cancer of the prostate.
- the prostate is a gland in the male reproductive system that surrounds the urethra just below the bladder. Most prostate cancer are slow growing. Cancerous cells may spread to other areas of the body, particularly the bones and lymph nodes. Prostate cancer may initially course no symptoms. In later stages, symptoms include pain or difficulty urinating, blood in the urine, or pain in the pelvis or back. Benign prostatic hyperplasia may produce similar symptoms. Other late symptoms include fatigue, due to low levels of red blood cells. Factors that increase the risk of prostate cancer include older age, family history and race. About 99% of cases occur after age 50. A first-degree relative with the disease increases the risk two- to three-fold.
- prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer.
- the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)).
- the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
- diagnosing prostate cancer means determining whether an individual shows signs of or suffers from prostate cancer.
- determining lymph node involvement in an individual suffering from prostate cancer means determining whether the lymph nodes are affected by the cancer.
- prostate cancer cells have spread from the prostate to the lymph nodes.
- the lymph node involvement (LNI) represents one of the most relevant prognostic factors in prostate cancer patients, where individuals with LNI exhibit an unfavourable natural hi story compared with their counterparts without nodal metastases. The presence of clinical nodal metastases is associated with detrimental oncologic outcomes. Thus, knowing whether lymph nodes are involved in prostate cancer or not is crucial for the determination and selection of treatment options and subsequent therapy.
- determining the course of prostate cancer means evaluating the development of prostate cancer over time, e.g. whether prostate cancer worsens in the individual, does not worsen/is stable in the individual, or improves in the individual over time.
- the term “classifying prostate cancer”, as used herein, means determining the stage of prostate cancer.
- the classification of prostate cancer allows to determine the size of the cancer and how far it has grown. Knowing the stage helps defining prognosis and is useful when selecting therapies.
- the most common system is the four-stage TNM system (abbreviated from tumor/nodes/metastases). Its components include the size of the tumor, the number of involved lymph nodes, and the presence of any other metastases.
- the most important distinction made by any staging system is whether the cancer is confined to the prostate.
- Tl The tumor cannot be felt during digital rectal exam (DRE) or seen during imaging (e.g. a computed tomography (CT) scan or transrectal ultrasound). It may be found when surgery is done for another medical condition.
- DRE digital rectal exam
- CT computed tomography
- o Tla The tumor is discovered accidentally during a surgical procedure used to treat benign prostatic hyperplasia (BPH), which is the abnormal growth of benign prostate cells. Cancer is only found in 5 percent or less of the tissue removed.
- O Tib The tumor is found accidentally during BPH surgery. Cancer cells are detected in more than 5 percent of the tissue removed.
- o Tic The tumor is found during a needle biopsy that was performed because of an elevated prostate-specific antigen (PSA) level.
- PSA prostate-specific antigen
- T2 The tumor appears to be confined to the prostate. Due to the size of the tumor, the doctor can feel it during the DRE. The cancer may also be seen with imaging.
- o T2a The tumor has invaded one-half (or less) of one side of the prostate.
- o T2b The tumor has spread to more than one-half of one side of the prostate, but not to both sides.
- o T2c The cancer has invaded both sides of the prostate.
- T3 The tumor has grown outside the prostate. It may have spread to the seminal vesicles.
- o T3a The tumor has developed outside the prostate; however, it has not spread to the seminal vesicles.
- o T3b The tumor has spread to the seminal vesicles.
- T4 The tumor has spread to tissues next to the prostate other than the seminal vesicles.
- the cancer may be growing in the rectum, bladder, urethral sphincter (muscle that controls urination) and/or pelvic wall.
- the lymph nodes may also be affected. Specifically, NO indicates that the tumor has not spread to nearby lymph nodes, while N1 means that it has.
- determining the risk for recurrence/relapse of prostate cancer in an individual means evaluating whether an individual which is in remission (no symptoms or signs of disease) becomes ill again.
- determining the risk for recurrence/relapse of prostate cancer in an individual means evaluating whether prostate cancer comes back (recurred) after an initial treatment. In this case, further treatment can be helpful. The follow-up treatment, however, depends on where the prostate cancer is thought to be and what treatment(s) the individual already had.
- radiation therapy might be an option, sometimes along with hormone therapy.
- treatment options might include cryotherapy or radical prostatectomy, but when these treatments are done after radiation, they carry a higher risk for side effects such as incontinence. Having radiation therapy again is usually not an option because of the increased potential for serious side effects, although in some cases brachytherapy may be an option as a second treatment after external radiation.
- Another option for some individuals might be active surveillance instead of active treatment. Prostate cancer often grows slowly, so even if it does come back, it might not cause problems for many years, at which time further treatment could then be considered.
- the term “individual”, as used herein, refers to a subject suspected to be affected by prostate cancer.
- the individual may be diagnosed to be affected by prostate cancer, i.e. diseased, or may be diagnosed to be not affected by prostate cancer, i.e. healthy.
- the term “individual”, as used herein, refers to a subject which is affected by prostate cancer, i.e. diseased.
- the individual may be monitored to determine whether prostate cancer develops over time or not.
- the individual may be retested for prostate cancer and may be diagnosed as having developed an advanced form/stage/class of prostate cancer.
- the term “individual”, as used herein refers to a subject diagnosed as having prostate cancer with or without lymph node involvement.
- the term “individual”, as used herein, refers to a subject suffering from a relapse/recurrence of prostate cancer.
- an individual that is diagnosed as being healthy i.e. not suffering from prostate cancer, may possibly suffer from another disease or condition not tested/known.
- the individual may be any mammal, including both a human and another mammal, e.g. an animal such as a rabbit, mouse, rat, or monkey. Human individuals specifically males are particularly preferred.
- control subject refers to a subject known to be not affected by prostate cancer (negative control), i.e. healthy.
- the term “(control) subject”, as used herein, also refers to a subject known to be affected by prostate cancer (positive control), i.e. diseased.
- Said (control) subject may have developed an advanced form/stage/class of prostate cancer.
- the (control) subject is a (control) subject with prostate cancer of a specific class (e.g. Tl, T2, T3, or T4, specifically Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, or T4).
- control subject refers to a subject know to have prostate cancer with or without lymph node involvement.
- control subject refers to a successfully treated prostate cancer subject or to a subject known to not experiencing a relapse/recurrence of prostate cancer.
- a (control) subject which is known to be healthy, i.e. not suffering from a prostate cancer, may possibly suffer from another disease or condition not tested/known.
- the (control) subject may be any mammal, including both a human and another mammal, e.g. an animal such as a rabbit, mouse, rat, or monkey. Human (control) subjects specifically males are particularly preferred.
- treatment refers to any therapy which improves the health status and/or prolongs (increases) the lifespan of an individual suffering from a disease or condition, in particular from cancer such as prostate cancer.
- Said therapy may eliminate the disease or condition in an individual, arrest or slow the development of a disease in an individual, inhibit or slow the development of a disease in an individual, decrease the frequency or severity of symptoms in an individual, and/or decrease the recurrence in an individual who currently has or who previously has had a disease.
- the treatment of a prostate cancer is preferably selected from the group consisting of surgery, chemotherapy, targeted therapy, immunotherapy, oncolytic viral therapy, vaccination therapy, radiotherapy, laser therapy, hyperthermia therapy, cryotherapy, and administration of a drug, or is a combination thereof.
- level refers to an amount (measured for example in grams, mole, or ion counts) or concentration (e.g. absolute or relative concentration) of the at least one biomarker claimed herein.
- concentration e.g. absolute or relative concentration
- level also comprises scaled, normalized, or scaled and normalized amounts or values.
- the level may also be a cut-off level.
- the level is an expression level.
- eukaryotic Initiation Factor refers to a molecule which is involved in the initiation phase of eukaryotic translation. This factor helps to stabilize the formation of the functional ribosome around the start codon and also provides regulatory mechanisms in translation initiation.
- eukaryotic Initiation Factor covers elF RNA transcripts (RNA transcript variants) such as mRNAs including splice variants of these transcripts and elF proteins encoded thereby.
- RNA transcript variants such as mRNAs including splice variants of these transcripts and elF proteins encoded thereby.
- the level of the elFs may be determined by measuring mRNA or protein levels.
- eukaryotic Initiation Factor (elF) also covers elF isoforms. These elF isoforms are members of a set of highly similar molecules, in particular proteins, that perform the same or similar biological role.
- eukaryotic Elongation Factor refers to a molecule that functions at the ribosome during protein synthesis to facilitate translational from the formation of the first to the last peptide bond of a growing polypeptide.
- eukaryotic Elongation Factor covers eEF RNA transcripts (RNA transcript variants) such as mRNAs including splice variants of these transcripts and eEF proteins encoded thereby.
- the level of the eEFs may be determined by measuring mRNA or protein levels.
- eukaryotic Elongation Factor (eEF) also covers eEF isoforms. These eEF isoforms are members of a set of highly similar molecules, in particular proteins, that perform the same or similar biological role.
- MRRF Mitochondrial Ribosome Recycling Factor
- ATP-binding cassette sub-family E member 1 refers to a molecule which is a member of the superfamily of ATP-binding cassette (ABC) transporters.
- ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the OABP subfamily. Alternatively referred to as the RNase L inhibitor, this protein functions to block the activity of ribonuclease L. Activation of ribonuclease L leads to inhibition of protein synthesis in the 2-5A/RNase L system, the central pathway for viral interferon action.
- biological sample refers to any biological sample from an individual or (control) subject comprising at least one of the biomarkers such as elFs and/or eEFs claimed herein.
- the biological sample may be a body fluid sample, e.g. a blood sample or urine sample, or a tissue sample.
- Biological samples may be mixed or pooled, e.g. a sample may be a mixture of a blood sample and a urine sample.
- Said biological samples may be provided by removing a body fluid from an individual or (control) patient, but may also be provided by using a previously isolated sample.
- a blood sample may be taken from an individual or (control) subject by conventional blood collection techniques.
- the biological sample e.g.
- urine sample or blood sample may be obtained from an individual or (control) subject prior to the initiation of a therapeutic treatment, during the therapeutic treatment, and/or after the therapeutic treatment.
- the biological sample is obtained from at least one (control) subject, e.g. from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 500, or 1.000 (control) subject(s), it is designated as a “reference biological sample”.
- the reference biological sample is from the same source than the biological sample of the individual to be tested, e.g. both are blood samples or urine samples. It is further preferred that both are from the same species, e.g. from a human.
- the measurements of the reference biological sample and the biological sample of the individual to be tested are identical, e.g. both have an identical volume. It is particularly preferred that the reference biological sample and the biological sample are from individuals/(control) subjects of the same sex and similar age, e.g. no more than 2 years apart from each other.
- body fluid sample refers to any liquid sample derived from the body of an individual or (control) subject containing at least one of the biomarkers such as elFs and/or eEFs claimed herein.
- Said body fluid sample may be a urine sample, blood sample, sputum sample, breast milk sample, cerebrospinal fluid (CSF) sample, cerumen (earwax) sample, gastric juice sample, mucus sample, lymph sample, endolymph fluid sample, perilymph fluid sample, peritoneal fluid sample, pleural fluid sample, saliva sample, sebum (skin oil) sample, semen sample, sweat sample, tears sample, cheek swab, vaginal secretion sample, liquid biopsy, or vomit sample including components or fractions thereof.
- CSF cerebrospinal fluid
- cerumen earwax
- gastric juice sample gastric juice sample
- mucus sample mucus sample
- lymph sample endolymph fluid sample
- perilymph fluid sample perilymph fluid sample
- body fluid sample also encompasses body fluid fractions, e.g. blood fractions, urine fractions or sputum fractions.
- Body fluid samples may be mixed or pooled.
- a body fluid sample may be a mixture of a blood and a urine sample or a mixture of a blood and cerebrospinal fluid sample.
- Said body fluid sample may be provided by removing a body liquid from an individual or (control) subject, but may also be provided by using previously isolated body fluid sample material.
- the body fluid sample allows for a non- invasive analysis of an individual or (control) subject. It is further preferred that the body fluid sample has a volume of between 0.01 and 20 ml, more preferably of between 0.1 and 10 ml, even more preferably of between 0.5 and 8 ml, and most preferably of between 1 and 5 ml.
- blood sample encompasses a whole blood sample or a blood fraction sample such as a blood serum or blood plasma sample. It is preferred that the blood serum or plasma sample has a volume of between 0.01 and 20 ml, more preferably of between 0.1 and 10 ml, even more preferably of between 0.5 and 8 ml and most preferably of between 1 and 5 ml.
- kit of parts in short: kit
- kit is understood to be any combination of at least some of the components identified herein, which are combined, coexisting spatially, to a functional unit, and which can contain further components.
- Said kit may allow point-of-care testing (POCT).
- POCT point-of-care testing
- POCT point-of-care testing
- POCT is often accomplished through the use of transportable, portable, and handheld instruments and test kits.
- Small bench analyzers or fixed equipment can also be used when a handheld device is not available - the goal is to collect the specimen and obtain the results in a very short period of time at or near the location of the individual so that the treatment plan can be adjusted as necessary before the individual leaves the hospital.
- prostate cancer Early diagnosis of prostate cancer often increases the likelihood of successful treatment or cure of such disease.
- the problem is that the majority of prostate cancer patients are asymptomatic. Diagnosis in such cases is based on abnormalities detected by screening for serum levels of prostate-specific antigen (PSA) or findings on digital rectal examination (DRE).
- PSA prostate-specific antigen
- DRE digital rectal examination
- prostate cancer can be an incidental pathologic finding when tissue is removed during transurethral resection to manage obstructive symptoms from benign prostatic hyperplasia.
- patients may present with symptoms of primary or secondary/metastatic disease or due to the generalized effect of malignancy.
- Symptoms of the primary disease are, in some cases, attributable to those originating from the prostate volume rather than cancer symptoms per se. These symptoms usually include lower urinary tract symptoms (LUTS), urine retention, and/or hematuria. However, patients with benign prostatic hyperplasia alone can also have similar symptoms.
- LUTS lower urinary tract symptoms
- urine retention urine retention
- hematuria hematuria
- Symptoms of advanced disease result from any combination of lymphatic, hematogenous, or contiguous local spread. Skeletal manifestations are especially common with more than 70% of people who die of prostate carcinoma having metastatic disease in their bones.
- Prostate cancer has a strong capability of metastasizing to bone through the hematogenous route, and symptoms will depend on the site of metastasis with manifestation as localized bone pain.
- the most common bones involved include those of the axial skeleton such as spine and the pelvis, although any bone may be affected. Beside bones, liver and lungs can also be affected. Lymphatic spread results in lymph node metastasis.
- Advanced prostate cancer can also be associated with generalized symptoms of malignancy include lethargy, weight loss and anemia, which may be secondary to marrow infiltration or destruction by metastasis.
- prostate cancer early and symptom-independent diagnosis of prostate cancer is highly desirable. As progression of prostate cancer is highly heterogeneous, there remains a need for correct prostate cancer classification which is a critical step in the management of the disease.
- the present inventors have identified new biomarkers which allow an improved diagnosis, monitoring, and classification of prostate cancer. They also allow determination of recurrent prostate cancer.
- the present invention relates to a (an in vitro) method of diagnosing prostate cancer in an individual comprising the step of determining the level of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers) in a biological sample from an individual, wherein the at least one biomarker (e.g.
- eukaryotic Initiation Factor 4G1 eIF4Gl
- eEFID eukaryotic Elongation Factor ID
- MRRF Mitochondrial Ribosome Recycling Factor
- the individual is suspected of having prostate cancer.
- the level(s) of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21 biomarker(s), or of 22 biomarkers mentioned above is (are) determined.
- the level of the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers) is compared to a reference level of said at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers).
- a reference level of said at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers.
- biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers
- the level of the at lest one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers
- a reference level of said at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers
- the at least one biomarker e.g.
- eukaryotic Initiation Factor 4G1 eIF4Gl
- eEFID eukaryotic Elongation Factor ID
- MRRF Mitochondrial Ribosome Recycling Factor
- the reference level may be any level which allows to determine whether an individual suffers from prostate cancer or not. It may be obtained from a (control) subject (i.e. a subject different from the individual to be tested such as a healthy subject and/or a subject known to have prostate cancer) or from the same individual. In the latter case, the individual may be retested for prostate cancer, e.g. in the form of a longitudinal monitoring. It may be determined that the individual is now affected by prostate cancer or still not affected by prostate cancer.
- a control subject i.e. a subject different from the individual to be tested such as a healthy subject and/or a subject known to have prostate cancer
- the individual may be retested for prostate cancer, e.g. in the form of a longitudinal monitoring. It may be determined that the individual is now affected by prostate cancer or still not affected by prostate cancer.
- the reference level is the level determined by measuring one or more reference biological sample(s), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 reference biological sample(s), from one or more subject(s) known to be healthy /known to have no prostate cancer, e.g.
- the reference level is the level determined by measuring between 2 and 500 reference biological samples from between 2 and 500 subjects known to be healthy/known to have no prostate cancer. More particularly, the reference level is determined by measuring between 50 and 500 reference biological samples from between 50 and 500 subjects known to be healthy/known to have no prostate cancer. Even more particularly, the reference level is determined by measuring between 100 and 500 reference biological samples from between 100 and 500 subjects known to be healthy/known to have no prostate cancer.
- Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof.
- the level of the at least one biomarker is at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold or 1.5- fold, and most preferably at least 2.0-fold or 3.0-fold below/above the reference level.
- the level of the at least one biomarker is at least 0.6-fold, at least 0.7-fold, at least 0.8- fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold below/above the reference level.
- the level of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6 biomarker(s) or 7 biomarkers) selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, eIF3H, and MRRF is determined.
- at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6 biomarker(s) or 7 biomarkers
- biomarkers selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, and eIF3H or combinations of biomarkers selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, and eIF3H are shown in Figure 19.
- the biomarker is MRRF or MRRF is part of the combinations shown in Figure 19. It is most preferred that the level of at least one biomarker (e.g.
- biomarker 1, 2, 3 biomarker(s) or 4 biomarkers) selected from the group consisting of eIF4Gl, eIF2B5, eIF3B, and MRRF is determined.
- Specific biomarkers selected from the group consisting of eIF4Gl, eIF2B5, and eIF3B or combinations of biomarkers selected from the group consisting of eIF4Gl, eIF2B5, and eIF3B are shown in Figure 19.
- the biomarker is MRRF or MRRF is part of the combinations shown in Figure 19.
- the present invention relates to a (an in vitro) method of determining lymph node involvement in an individual suffering from prostate cancer comprising the step of: determining the level of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) in a biological sample from an individual, wherein the at least one biomarker (e.g.
- At least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2.
- eIF3D eukaryotic Initiation Factor 3D
- eIF3L eukaryotic Initiation Factor 3M
- eIF4B eIF5A
- eIF5B eukaryotic Elongation Factor 1A1
- eEFlAl eukaryotic Elongation Factor 1A1
- the individual is suspected of having prostate cancer with lymph node involvement or without lymph node involvement.
- the level(s) of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8 biomarker(s), or of 9 biomarkers mentioned above is (are) determined.
- the level of the at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers
- a reference level of said at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers.
- the present invention relates to a (an in vitro) method of determining lymph node involvement in an individual suffering from prostate cancer comprising the steps of
- biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers
- the at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers
- a reference level of said at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers
- At least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2.
- eIF3D eukaryotic Initiation Factor 3D
- eIF3L eukaryotic Initiation Factor 3M
- eIF4B eIF5A
- eIF5B eukaryotic Elongation Factor 1A1
- eEFlAl eukaryotic Elongation Factor 1A1
- lymph nodes are involved in an individual suffering from prostate cancer or not. If the lymph nodes are involved, prostate cancer cells have spread from the prostate to the lymph nodes.
- the lymph node involvement (LNI) represents one of the most relevant prognostic factors in prostate cancer patients, where individuals with LNI exhibit an unfavourable natural history compared with their counterparts without nodal metastases. The presence of clinical nodal metastases is associated with detrimental oncologic outcomes. Thus, knowing whether lymph nodes are involved in prostate cancer is crucial for the determination and selection of treatment options and subsequent therapy.
- the reference level may be any level which allows to determine whether lymph nodes are involved in an individual suffering from prostate cancer or not.
- the reference level is the level determined by measuring one or more reference biological sample(s), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 reference biological sample(s), from one or more subject(s) known to have prostate cancer without lymph node involvement, e.g.
- the reference level is the level determined by measuring between 2 and 500 reference biological samples from between 2 and 500 subjects known to have prostate cancer without lymph node involvement. More particularly, the reference level is determined by measuring between 50 and 500 reference biological samples from between 50 and 500 subjects known to have prostate cancer without lymph node involvement. Even more particularly, the reference level is determined by measuring between 100 and 500 reference biological samples from between 100 and 500 subjects known to have prostate cancer without lymph node involvement.
- Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof. It is more preferred that the level of the at least one biomarker below the reference level (determined by measuring one or more reference biological samples from one or more subjects known to have prostate cancer without lymph node involvement) indicates that the individual suffers from prostate cancer with lymph node involvement.
- the reference level is the level determined by measuring one or more reference biological sample(s), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,
- the reference level is the level determined by measuring between 2 and 500 reference biological samples from between 2 and 500 subjects known to have prostate cancer with lymph node involvement. More particularly, the reference level is determined by measuring between 50 and 500 reference biological samples from between 50 and 500 subjects known to have prostate cancer with lymph node involvement. Even more particularly, the reference level is determined by measuring between 100 and 500 reference biological samples from between 100 and 500 subjects known to have prostate cancer with lymph node involvement.
- Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof. It is more preferred that the level of the at least one biomarker above the reference level (determined by measuring one or more reference biological samples from one or more subjects known to have prostate cancer with lymph node involvement) indicates that the individual suffers from prostate cancer without lymph node involvement.
- the level of the at least one biomarker is at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold or 1.5- fold, and most preferably at least 2.0-fold or 3.0-fold below/above the reference level.
- the level of the at least one biomarker is at least 0.6-fold, at least 0.7-fold, at least 0.8- fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold below/above the reference level.
- a prostate cancer without lymph node involvement can also be designated as prostate cancer of NO.
- a prostate cancer with lymph node involvement can also be designated as prostate cancer of Nl.
- prostate cancer is usually prostate cancer of T4.
- the present invention relates to a (an in vitro) method of monitoring/determining the course of prostate cancer in an individual comprising the step of: determining the level of at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) in a biological sample from an individual, wherein the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
- eIF3C eukaryotic Initiation Factor 3C
- ABCE1 ATP Binding Cassette Subfamily E Member 1
- the individual suffers from prostate cancer.
- the level(s) of at least 1, at least 2, at least 3, at least 4 biomarker(s), or of 5 biomarkers mentioned above is (are) determined.
- the level of the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) is compared to a reference level of said at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers).
- a reference level of said at least one biomarker e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers.
- biomarker e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers
- the at least one biomarker e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers
- the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
- eIF3C eukaryotic Initiation Factor 3C
- eIF5A eIF5A
- eIF3H eIF5B
- ATP Binding Cassette Subfamily E Member 1 ABCE1
- the above comparison allows to monitor/determine the course of the prostate cancer in the individual suffering from prostate cancer. It may be determined that prostate cancer worsens in the individual, that prostate cancer does not worsen/is stable in the individual, or that prostate cancer improves in the individual.
- the reference level may be any level which allows to monitor/determine the course of the prostate cancer in the individual suffering from prostate cancer. It may be obtained from a (control) subject (i.e. a subject different from the individual to be tested such as a subject known to have prostate cancer).
- the reference level is the level determined by measuring one or more reference biological sample(s), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
- the reference level is the level determined by measuring between 2 and 500 reference biological samples from between 2 and 500 subjects known to have prostate cancer. More particularly, the reference level is determined by measuring between 50 and 500 reference biological samples from between 50 and 500 subjects known to have prostate cancer. Even more particularly, the reference level is determined by measuring between 100 and 500 reference biological samples from between 100 and 500 subjects known to have prostate cancer.
- the subject(s) known to have prostate cancer may have, for example, prostate cancer of Tl, T2, T3, or T4, specifically Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, or T4.
- the level of the at least one biomarker selected from the group consisting of eIF3C, eIF3H, and ABCE1 above the reference level indicates that prostate cancer progresses/worsens in the individual, and/or the at least one biomarker selected from the group consisting of eIF5A and eIF5B below the reference level indicates that prostate cancer progresses/worsens in the individual.
- the reference level may be any level which allows to monitor/determine the course of the prostate cancer in the individual suffering from prostate cancer. It may be obtained from a (control) subject (i.e. a subject different from the individual to be tested such as a subject known to have prostate cancer). It may also be obtained from the same individual.
- said determining comprises determining the level of the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) in a biological sample from an individual at a first point in time and in at least one further biological sample from the (same) individual at a later point in time and comparing said levels determined at the different time points.
- the present invention relates to a (an in vitro) method of determining the course of prostate cancer in an individual comprising the steps of
- biomarker e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers
- the at least one biomarker e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers
- the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
- This proceeding allows to monitor/determine the course of prostate cancer in an individual having prostate cancer over an extended period of time, such as months or years, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 month(s), 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 year(s).
- months or years e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 month(s), 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 year(s).
- the above comparison allows to monitor/determine the course of the prostate cancer in the individual suffering from prostate cancer. It may be determined that prostate cancer worsens in the individual, that prostate cancer does not worsen/is stable in the individual, or that prostate cancer improves in the individual.
- the level of the at least one biomarker selected from the group consisting of eIF3C, eIF3H, and ABCE1 which
- (iii) decreases over time indicates that prostate cancer improves in the individual.
- the individual had prostate cancer at the first point in time and the level which increases over time indicates that prostate cancer is worsening in the individual
- the individual had prostate cancer at the first point in time and the level which does not change over time indicates that prostate cancer is not progressing in the individual
- the individual had prostate cancer at the first point in time and the level which decreases over time indicates that prostate cancer is improving in the individual.
- the individual had prostate cancer at the first point in time and the level which decreases over time indicates that prostate cancer is worsening in the individual, the individual had prostate cancer at the first point in time and the level which does not change over time indicates that prostate cancer is not progressing in the individual, or the individual had prostate cancer at the first point in time and the level which increases over time indicates that prostate cancer is improving in the individual.
- the increase may be at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1- fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold over time.
- the decrease may be at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5- fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold over time.
- “Stable”, as mentioned above, means that the level varies over time between 0 and ⁇ 20%, e.g. 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 19.9, 19.99, or 19.999%. “Stable” in this respect may also mean that the detected level variation is within the accuracy of a measurement. The accuracy of a measurement depends on the measurement method used. Preferably, the level is constant over time.
- the time period between the first point in time and the later point(s) in time preferably amounts to at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days (1 week), at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months (1 year), at least 24 months (2 years), at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, or at least 10 years.
- the individual may be routinely checked, e.g. once or twice a year.
- the individual may be (re)tested at 2, 3, 4, 5, 6 7, 8, 9, or 10 time points (first point in time and further point(s) in time).
- the treatment of this disease can be monitored.
- the individual receives, has received, or had received a therapeutic treatment of prostate cancer.
- the therapeutic treatment of prostate cancer is preferably selected from the group consisting of surgery, chemotherapy, targeted therapy, immunotherapy, oncolytic viral therapy, vaccination therapy, radiotherapy, laser therapy, hyperthermia therapy, cryotherapy, and administration of a drug, or is a combination thereof.
- the individual may receive a treatment during the complete monitoring process (e.g. the administration of a drug) or may receive a treatment before, at, or after a first point in time (e.g. the administration of a drug) and may be retested at a later point in time.
- said first point in time may be before the initiation of a treatment and said later point in time may be during the treatment and/or after the treatment.
- an increased level of the at least one biomarker can be decreased or a decreased level of the at least one biomarker can be increased. In this way, the (overall) condition of the individual having prostate cancer can be improved.
- the present invention relates to a method of classifying prostate cancer in an individual comprising the step of determining the level of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers) in a biological sample from an individual, wherein the at least one biomarker (e.g.
- eukaryotic Initiation Factor 3C eukaryotic Initiation Factor 3C
- eIF3C eukaryotic Initiation Factor 3C
- eIF5A eIF5A
- eIF5B eIF5A
- eIF4H eukaryotic Initiation Factor 3D
- eIF3G eIF3L
- eIF3I eIF3J
- eIF2B3, eIF2Sl elFlAX
- eIF2B4E eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
- the individual suffers from prostate cancer.
- the level(s) of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18 biomarker(s), or of 19 biomarkers mentioned above is (are) determined.
- the level of the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers) is compared to a reference level of said at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers).
- a reference level of said at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers.
- biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers
- the level of the at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers
- the at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
- eukaryotic Initiation Factor 3C eukaryotic Initiation Factor 3C
- eIF3C eukaryotic Initiation Factor 3C
- eIF5A eIF5A
- eIF5B eIF5A
- eIF4H eukaryotic Initiation Factor 3D
- eIF3G eIF5G
- eIF3L eIF3L
- eIF3I eIF3J
- eIF2B3, eIF2Sl elFlAX
- eIF2B4E eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
- the above comparison allows to classify whether the individual suffers from prostate cancer of Tl, T2, T3, or T4. More particularly, the above comparison allows to classify whether the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, or T4.
- the reference level may be any level which allows to classify the individual, e.g. as individual suffering from prostate cancer of Tl, T2, T3, or T4, preferably of Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, or T4.
- the reference level is the level determined by measuring one or more reference biological sample(s), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
- the reference level is the level determined by measuring between 2 and 500 reference biological samples from between 2 and 500 subjects known to have prostate cancer of Tl, T2, T3, and/or T4, specifically Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, and/or T4. More particularly, the reference level is determined by measuring between 50 and 500 reference biological samples from between 50 and 500 subjects known to have prostate cancer of Tl, T2, T3, and/or T4, specifically Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, and/or T4.
- the reference level is determined by measuring between 100 and 500 reference biological samples from between 100 and 500 subjects known to have prostate cancer of Tl, T2, T3, and/or T4, specifically Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, and/or T4.
- Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof. It is more preferred that
- the level of eIF3C above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4
- the level of eIF3C above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b, or T4
- the level of eIF3C above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of T4
- the level of eIF3C below the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b, the level of
- the level of eIF3H above the reference level of eIF3H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4
- the level of eIF3H above the reference level of eIF3H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4
- the level of eIF3H below the reference level of eIF3H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer T la, Tib, Tic, T2a, T2b, or T2c, or T3a, or the level of eIF3H below the reference level of eIF3H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from
- the level of eIF5A below the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, the level of eIF5A below the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of eIF5A below the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b or T4, the level of eIF5A above the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T
- the level of eIF5B below the reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, the level of eIF5B below the reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of eIF5B below the reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b or T4, or the level of eIF5B above the reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b and below e reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T
- the level of eIF5 above the reference level of eIF5 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2c, T3a, T3b, or T4, or the level of eIF5 below the reference level of eIF5 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b,
- the level of eIF4H above the reference level of eIF4H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of T4, or the level of eIF4H below the reference level of eIF4H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b,
- the level of eIF3D below the reference level of eIF3D determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or the level of eIF3D above the reference level of eIF3D determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
- the level of eIF3G below the reference level of eIF3G determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or the level of eIF3G above the reference level of eIF3G determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
- the level of eIF3L below the reference level of eIF3L determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or the level of eIF3L above the reference level of eIF3L determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
- the level of eIF3I below the reference level of eIF3I determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, or the level of eIF3I above the reference level of eIF3I determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
- the level of eIF3 J below the reference level of eIF3 J determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b or T4, or the level of eIF3 J above the reference level of eIF3 J determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
- the level of eIF2B3 below the reference level of eIF2B3 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T3a, T3b, or T4, or the level of eIF2B3 above the reference level of eIF2B3 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
- the level of eEFl Al below the reference level of eEFl Al determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or the level of eEFl Al above the reference level of eEFl Al determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
- the level of eEF2 below the reference level of eEF2 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or the level of eEF2 above the reference level of eEF2 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
- the level of elFl AX above the reference level of elFl AX determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2a, T2c, T3a, T3b, or T4, or the level of elFl AX below the reference level of elFl AX determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b,
- the level of eIF2Sl above the reference level of eIF2Sl determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2a, T2c, T3a, T3b, or T4, or the level of eIF2Sl below the reference level of eIF2Sl determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b,
- the level of eIF2B4 below the reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, the level of eIF2B4 below the reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of eIF2B4 below the reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b or T4, or the level of eIF2B4 above the reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b and below e reference level of eIF2B4 determined by measuring one or more reference
- the level of eIF4E above the reference level of eIF4E determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2c, T3a, T3b, or T4
- the level of eIF4E above the reference level of eIF4E determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of T4
- the level of eIF4E below the reference level of eIF4E determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b, or the level of eIF4E below the reference level of eIF4E determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, T
- the level of ABCE1 above the reference level of ABCE1 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2c, T3a, T3b, or T4
- the level of ABCE1 above the reference level of ABCE1 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4
- the present invention relates to a method of determining the risk for recurrence/relapse of prostate cancer in an individual comprising the step of determining the level of at least one biomarker (e.g. 1 or 2 biomarker(s)) in a biological sample from an individual, wherein the at least one biomarker (e.g. 1 or 2 biomarker(s)) is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
- eukaryotic Initiation Factor 4G1 eukaryotic Initiation Factor 4G1
- MRRF Mitochondrial Ribosome Recycling Factor
- the individual had received a therapeutic treatment of prostate cancer. Specifically, the individual was successfully treated with the therapeutic treatment of prostate cancer.
- the biological sample is isolated after the therapeutic treatment of prostate cancer.
- the therapeutic treatment of the prostate cancer is selected from the group consisting of surgery, chemotherapy, targeted therapy, immunotherapy, oncolytic viral therapy, vaccination therapy, radiotherapy, laser therapy, hyperthermia therapy, cryotherapy, and administration of a drug, or is a combination thereof.
- the level of the at least one biomarker is compared to a reference level of said at least one biomarker.
- the present invention relates to a (an in vitro) method of determining the risk for recurrence/relapse of prostate cancer in an individual comprising the steps of
- biomarker e.g. 1 or 2 biomarker(s)
- the at least one biomarker e.g. 1 or 2 biomarker(s)
- a reference level of said at least one biomarker e.g. 1 or 2 biomarker(s)
- the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
- the above comparison allows to evaluate whether an individual which is in remission (no symptoms or signs of disease) becomes ill again.
- the above comparison allows to evaluate whether prostate cancer comes back (recurred) after an initial treatment. In this case, further treatment can be helpful.
- the follow-up treatment depends on where the prostate cancer is thought to be and what treatment(s) the individual already had.
- radiation therapy might be an option, sometimes along with hormone therapy.
- treatment options might include cryotherapy or radical prostatectomy, but when these treatments are done after radiation, they carry a higher risk for side effects such as incontinence. Having radiation therapy again is usually not an option because of the increased potential for serious side effects, although in some cases brachytherapy may be an option as a second treatment after external radiation.
- Another option for some individuals might be active surveillance instead of active treatment. Prostate cancer often grows slowly, so even if it does come back, it might not cause problems for many years, at which time further treatment could then be considered.
- the reference level may be any level which allows to determine whether prostate cancer recurred again in the individual. It may be obtained from (control) subjects (i.e. subjects different from the individual to be tested such as healthy subjects or successfully treated prostate cancer subjects/prostate cancer subjects with no recurrence). The reference level may also be obtained from the same individual.
- the reference level is the level of the at least one biomarker determined by measuring one or more reference biological sample(s), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 reference biological sample(s), from one or more healthy subject(s), successfully treated prostate cancer subject(s), or prostate cancer subject(s) with no recurrence, e.g.
- the reference level is from the same individual, e.g. after initial treatment.
- Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof.
- the level of the at least one biomarker above the reference level indicates a risk of the individual for relapse/recurrence of prostate cancer.
- the level of the at least one biomarker is at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold or 1.5- fold, and most preferably at least 2.0-fold or 3.0-fold above the reference level.
- the level of the at least one biomarker is at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6- fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold above the reference level.
- the individual referred to in the methods of the first to fifth aspect of the present invention may be any mammal, including both a human and another mammal, e.g. an animal such as a rabbit, mouse, rat, or monkey. Human individuals such as males are particularly preferred.
- the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
- the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample and a combination thereof.
- the blood sample is a whole blood sample or a blood fraction sample.
- the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
- the biological sample and the reference biological sample used are identical.
- the aforementioned samples are pre-treated before they are used in the methods of the first to fifth aspect of the present invention.
- Said pre-treatment may include treatments required to separate the at least one biomarker described herein, or to remove excessive material or waste.
- pre-treatments may aim to sterilize samples and/or remove contaminants such as undesired cells, bacteria, or viruses. Suitable techniques comprise centrifugation, extraction, fractioning, ultrafiltration, protein precipitation followed by filtration and purification and/or enrichment of compounds.
- other pre-treatments are carried out in order to provide the at least one biomarker described herein in a form or concentration suitable for analysis.
- the biological sample used to determine the level of the at least one biomarker is a tissue sample, e.g. tumor tissue sample (obtainable e.g. by biopsy), or a body fluid sample.
- the biomarkers of the present invention can be found in the tissue affected with the tumor and in body fluids like blood and blood components (e.g. plasma or serum).
- the level of the at least one biomarker is determined by measuring mRNA or protein levels.
- the level of the at least one biomarker in the methods of the first to fifth aspect of the present invention can be determined either by measuring a mRNA molecule encoding the at least one biomarker or by measuring the at least one biomarker in protein form.
- Methods to determine mRNA levels and protein levels in a sample are well known.
- mRNA expression levels are usually measured by polymerase chain reaction (PCR), in particular by reverse transcription quantitative polymerase chain reaction (RT-PCR and qPCR) or real-time PCR.
- RT-PCR is used to create a cDNA from the mRNA.
- the cDNA may be used in a qPCR assay to produce fluorescence as the DNA amplification process progresses. This fluorescence is proportional to the original mRNA amount in the samples.
- Biomarkers are preferably determined using immunoassays. Such methods are based on the binding of an antibody, a derivative or a fragment thereof to its corresponding target (i.e. biomarker).
- Polyclonal and monoclonal antibodies can be used in such methods.
- Derivatives or fragments of antibodies include Fab fragments, F(ab')2 fragments, Fv fragments, single chain antibodies and single domain antibodies.
- Preferred immunoassays include Western blot, Immunohistochemistry, ELISA (enzyme-linked immunosorbent assay), radioimmunoassays, fluorescence resonance energy transfer (FRET) or time resolved-FRET (TR-FRET). It is particularly preferred to use antibodies and derivatives or fragments of antibodies which have been obtained from a non-human source. These antigen binding molecules can be of porcine, rabbit, murine, camel or rat origin. Of course, it is also possible to use antibodies and derivatives or fragments thereof which are recombinantly produced in plants or cell cultures, in particular microbial cell cultures (e.g. bacteria, yeast).
- microbial cell cultures e.g. bacteria, yeast
- the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
- the present invention relates to the (in vitro) use of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers) for diagnosing prostate cancer, wherein the at least one biomarker (e.g.
- eukaryotic Initiation Factor 4G1 eIF4Gl
- eEFID eukaryotic Elongation Factor ID
- MRRF Mitochondrial Ribosome Recycling Factor
- At least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6 biomarker(s) or 7 biomarkers) selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, eIF3H, and MRRF is (are) used for diagnosing prostate cancer.
- biomarkers selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, and eIF3H or combinations of biomarkers selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, and eIF3H are shown in Figure 19.
- the biomarker is MRRF or MRRF is part of the combinations shown in Figure 19. More particularly, at least one biomarker (e.g.
- biomarker 1, 2, 3 biomarker(s) or 4 biomarkers) selected from the group consisting of eIF4Gl, eIF2B5, eIF3B, and MRRF is determined. More particularly preferred biomarkers selected from the group consisting of eIF4Gl, eIF2B5, and eIF3B or combinations of biomarkers selected from the group consisting of eIF4Gl, eIF2B5, and eIF3B are shown in Figure 19.
- the biomarker is MRRF or MRRF is part of the combinations shown in Figure 19.
- the level of the at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers
- the level of the at least one biomarker is determined/analyzed in a biological sample from an individual.
- the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample, and a combination thereof.
- the blood sample is a whole blood sample or a blood fraction sample.
- the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
- the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
- the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
- the present invention relates to the (in vitro) use of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) for determining lymph node involvement in an individual suffering from prostate cancer, wherein the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2.
- eukaryotic Initiation Factor 3D eIF3D
- eIF3L eukaryotic Initiation Factor 3M
- eIF4B eIF5A
- eIF5B eukaryotic Elongation Fact
- the level of the at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers
- the level of the at least one biomarker is determined/analyzed in a biological sample from an individual.
- the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample, and a combination thereof.
- the blood sample is a whole blood sample or a blood fraction sample.
- the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
- the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
- the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
- the present invention relates to the (in vitro) use of at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) for determining the course of prostate cancer in an individual, wherein the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
- eIF3C eukaryotic Initiation Factor 3C
- eIF5A eukaryotic Initiation Factor 3A
- eIF3H eIF3H
- eIF5B ATP Binding Cassette Subfamily E Member 1
- the level of the at least one biomarker e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers
- the level of the at least one biomarker is determined/analyzed in a biological sample from an individual.
- the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample, and a combination thereof.
- the blood sample is a whole blood sample or a blood fraction sample.
- the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
- the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
- the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
- the present invention relates to the (in vitro) use of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers) for classifying prostate cancer in an individual, wherein the at least one biomarker (e.g.
- eukaryotic Initiation Factor 3C eukaryotic Initiation Factor 3C
- eIF3C eukaryotic Initiation Factor 3C
- eIF5A eIF5A
- eIF5B eIF5A
- eIF4H eukaryotic Initiation Factor 3D
- eIF3G eIF5G
- eIF3L eIF3L
- eIF3I eIF3J
- eIF2B3, eIF2Sl elFlAX
- eIF2B4E eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
- the level of the at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers
- the level of the at least one biomarker is determined/analyzed in a biological sample from an individual.
- the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample, and a combination thereof.
- the blood sample is a whole blood sample or a blood fraction sample.
- the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
- the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
- the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
- the present invention relates to the (in vitro) use of at least one biomarker (1 or 2 biomarkers(s)) for determining the risk for recurrence/relapse of prostate cancer in an individual, wherein the at least one biomarker (1 or 2 biomarkers(s)) is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
- eukaryotic Initiation Factor 4G1 eukaryotic Initiation Factor 4G1 (eIF4Gl)
- MRRF Mitochondrial Ribosome Recycling Factor
- the level of the at least one biomarker (e.g. 1 or 2 biomarker(s)) is determined/analyzed in a biological sample from an individual.
- the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample, and a combination thereof.
- the blood sample is a whole blood sample or a blood fraction sample.
- the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
- the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
- the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
- the present invention relates to a kit comprising means for determining the level of
- At least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eZF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF), (ii) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukin
- At least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1),
- At least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1), and/or
- At least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF), in a biological sample from an individual.
- eIF4Gl eukaryotic Initiation Factor 4G1
- MRRF Mitochondrial Ribosome Recycling Factor
- the means for determining the at least one biomarker under (i) are/are used for diagnosing prostate cancer in an individual.
- the at least one biomarker e.g. at least 1, 2, 3, 4, 5, 6 biomarker(s) or 7 biomarkers
- the at least one biomarker is selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, eIF3H, and MRRF.
- biomarkers selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, and eIF3H or combinations of biomarkers selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, and eIF3H are shown in Figure 19.
- the biomarker is MRRF or MRRF is part of the combinations shown in Figure 19. More particularly, at least one biomarker (e.g.
- biomarker 1, 2, 3 biomarker(s) or 4 biomarkers) selected from the group consisting of eIF4Gl, eIF2B5, eIF3B, and MRRF is determined. More particularly preferred biomarkers selected from the group consisting of eIF4Gl, eIF2B5, and eIF3B or combinations of biomarkers selected from the group consisting of eIF4Gl, eIF2B5, and eIF3B are shown in Figure 19.
- the biomarker is MRRF or MRRF is part of the combinations shown in Figure 19.
- the means for determining the at least one biomarker under (ii) are/are used for determining lymph node involvement in an individual suffering from prostate cancer. In this respect, it is referred to the second aspect of the present invention.
- the means for determining the at least one biomarker under (iii) are/are used for determining the course of prostate cancer in an individual. In this respect, it is referred to the third aspect of the present invention.
- the means for determining the at least one biomarker under (iv) are/are used for classifying prostate cancer in an individual. In this respect, it is referred to the fourth aspect of the present invention.
- the means for determining the at least one biomarker under (iv) are/are used for determining the risk for recurrence/relapse of prostate cancer in an individual. In this respect, it is referred to the fifth aspect of the present invention.
- said means may be primers or primer pairs allowing the detection of the above-mentioned biomarker(s) on the RNA transcript, e.g. mRNA, level and/or antibodies, antibody derivatives or fragments of antibodies allowing the detection of the above-mentioned biomarker(s) on the protein level.
- said means encompass dipstrips or dipsticks, e.g. urine or blood dipstrips or dipsticks.
- Said means are tools used to determine changes in individual’s urine or blood.
- a dipstrip or dipstick comprises different chemical pads or reagents which react (e.g. change color, in particular by applying an immune assay) when immersed in (e.g. blood or urine), and then removed from the biological sample (e.g. urine or blood sample). The result can be read after a few minutes, preferably after a few seconds.
- the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample.
- the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample, and a combination thereof.
- the blood sample is a whole blood sample or a blood fraction sample.
- the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
- the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
- the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
- kit is useful for conducting the methods of the first to fifth aspect of the present invention.
- the kit may further comprise
- Said data carrier may be a non-electronical data carrier, e.g. a graphical data carrier such as an information leaflet, an information sheet, a bar code or an access code, or an electronical data carrier such as a floppy disk, a compact disk (CD), a digital versatile disk (DVD), a microchip or another semiconductor-based electronical data carrier.
- the access code may allow the access to a database, e.g. an internet database, a centralized, or a decentralized database.
- the access code may also allow access to an application software that causes a computer to perform tasks for computer users or a mobile app which is a software designed to run on smartphones and other mobile devices.
- Said data carrier may further comprise a reference level of the at least one biomarker referred to herein.
- the data carrier comprises an access-code which allows the access to a database
- said reference level is deposited in this database.
- the data carrier may comprise information or instructions on how to carry out the methods according to the first to fifth aspect of the present invention.
- Said kit may also comprise materials desirable from a commercial and user standpoint including a buffer(s), a reagent(s) and/or a diluent(s) for determining the level mentioned above.
- Figure 1 Shows bar charts of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF) de-regulated between patients suffering from prostate cancer (prostate cancer tissue) and healthy control subjects (non-neoplastic tissue (NNT)).
- eEFID eukaryotic Elongation Factor ID
- eEFIG eEFIG
- NNT Mitochondrial Ribosome Recycling Factor
- Figure 2 Shows a histogram combined with a distribution and ROC curves combined with AUCs of eIF2Bl (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF2Bl with a mean area under the curve (AUC) value of 0.805.
- AUC mean area under the curve
- Figure 3 Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of eIF2B5 (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF2B5 with a mean area under the curve (AUC) value of 0.807.
- NNT non-neoplastic tissue
- ROC Receiver-Operating-Characteristic
- Figure 4 Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of eIF3B (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF3B with a mean area under the curve (AUC) value of 0.921.
- Figure 5 Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of eIF3C (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF3C with a mean area under the curve (AUC) value of 0.879.
- AUC mean area under the curve
- Figure 6 Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of eIF3H (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF3H with a mean area under the curve (AUC) value of 0.928.
- AUC mean area under the curve
- Figure 7 Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of eIF4Gl (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF4Gl with a mean area under the curve (AUC) value of 0.848.
- AUC mean area under the curve
- Figure 8 Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of MRRF (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of MRRF with a mean area under the curve (AUC) value of 0.930.
- Figure 9 Shows bar charts of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2 deregulated between patients suffering from prostate cancer without lymph node involvement (prostate cancer tissue of NO) and prostate cancer with lymph node involvement (prostate cancer tissue of Nl).
- eIF3D eukaryotic Initiation Factor 3D
- eIF3L eukaryotic Initiation Factor 3D
- eIF3M eIF3M
- eIF4B eIF5A
- eIF5B eukaryotic Elongation Factor 1A1
- eEFlAl eukaryotic Elongation Factor 1A1
- eEFlB2 eukaryotic Elongation Factor 1A1
- Figure 10 Shows bar charts of eukaryotic Initiation Factor 3C (eIF3C), efF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1) de-regulated between different stages of prostate cancer (prostate cancer tissue).
- eIF3C eukaryotic Initiation Factor 3C
- FIG. 11 Shows Receiver-Operating-Characteristic (ROC) curve of ABCE1 deregulated between prostate cancer stages T2B and T4 with a mean area under the curve (AUC) value of 0.800.
- ROC Receiver-Operating-Characteristic
- FIG. 12 Shows Receiver-Operating-Characteristic (ROC) curve of elFlAX deregulated between prostate cancer stages T2B and T4 with a mean area under the curve (AUC) value of 0.820.
- ROC Receiver-Operating-Characteristic
- FIG. 13 Shows Receiver-Operating-Characteristic (ROC) curve of eIF12Sl deregulated between prostate cancer stages T2B and T4 with a mean area under the curve (AUC) value of 0.800.
- ROC Receiver-Operating-Characteristic
- FIG. 14 Shows Receiver-Operating-Characteristic (ROC) curve of eIF5 de-regulated between prostate cancer stages T2B and T4 with a mean area under the curve (AUC) value of 0.850.
- ROC Receiver-Operating-Characteristic
- Figure 15 Shows bar charts with arithmetic means and standard deviation of eIF4Gl with no recurrence combined with high grade versus recurrence combined with high grade, and no recurrence and T3 or T4 versus recurrence and T3 or T4.
- High grade is defined as either (i) a primary Gleason Score of 3 and a secondary Gleason Score of 4 and a tertiary Gleason Score of 5, or (ii) a primary Gleason Score of 4, or (iii) a primary Gleason Score of 5.
- Figure 16 Shows bar charts with arithmetic means and standard deviation of MRRF with no recurrence combined with high grade versus recurrence combined with high grade, and no recurrence and T3 or T4 versus recurrence and T3 or T4, and no recurrence combined with the stage NO and high grade versus recurrence combined with NO and high grade.
- Figure 17 Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of eIF4Gl with recurrence (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF4Gl with a mean area under the curve (AUC) value of 0.865.
- Figure 18 Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of MRRF with recurrence (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF4Gl with a mean area under the curve (AUC) value of 0.853.
- NNT non-neoplastic tissue
- ROC Receiver-Operating-Characteristic
- FIG. 19 Preferred biomarkers selected from the group consisting of eIF2Bl, eIF2B5, eIF3B, eIF3C, eIF3H, and eIF4Gl or combinations (signatures) of biomarkers selected from the group consisting of eIF2Bl, eIF2B5, eIF3B, eIF3C, eIF3H, and eIF4Gl.
- the biomarker is MRRF or MRRF is part of the combinations.
- the TCGA PRAD Prostate Adenocarcinoma gene expression dataset (from https://gdac.broadinstitute.org) was used including different types of prostate tissues with clinical information about the patients (healthy cohort and cancer cohort) like Gleason score (primary, secondary, tertiary), subtype, T, N, M stages.
- Tissue Micro Arrays of prostate cancer tissue and non-neoplastic tissue (NNT) were immunohistochemically (antibody) treated against the translation factors. Based on the density * intensity scores (quickscores) were calculated.
- a p value ⁇ 0.05 was considered as statistically significant.
- Statistical analysis was performed with the common R library and was called from C# by using the R.NET package.
- Graph generation was performed using Microsoft Word and Excel.
- Graphs and diagrams were created with the common R library. Histograms with distributions of the quickscores were created based on PRAD tissues and non-neoplastic tissues.
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Abstract
The present invention relates to a method of diagnosing prostate cancer in an individual. Further, the present invention relates to a method of determining lymph node involvement in an individual suffering from prostate cancer. Furthermore, the present invention relates to a method of determining the course of prostate cancer in an individual. The present invention also relates to a method of classifying prostate cancer in an individual. In addition, the present invention relates to a method of determining the risk for recurrence/relapse of prostate cancer in an individual. Moreover, the present invention relates to a kit useful to carry out these methods.
Description
NOVEL BIOMARKERS FOR DETERMINING PROSTATE CANCER
The present invention relates to a method of diagnosing prostate cancer in an individual. Further, the present invention relates to a method of determining lymph node involvement in an individual suffering from prostate cancer. Furthermore, the present invention relates to a method of determining the course of prostate cancer in an individual. The present invention also relates to a method of classifying prostate cancer in an individual. In addition, the present invention relates to a method of determining the risk for recurrence/relapse of prostate cancer in an individual. Moreover, the present invention relates to a kit useful to carry out these methods.
BACKGROUND OF THE INVENTION
The prostate is a small walnut shaped gland in the pelvis of men. It is located next to the bladder and can be examined by getting a digital rectal exam. Prostate cancer is a form of cancer that develops in the prostate gland. It is the second-leading cause of cancer deaths for men in the United States.
Early diagnosis of prostate cancer often increases the likelihood of successful treatment or cure of such disease. The problem is that the majority of the prostate cancer patients are asymptomatic. Diagnosis in such cases is based on abnormalities detected by screening for serum levels of prostate-specific antigen (PSA) or findings on digital rectal examination (DRE). In addition, prostate cancer can be an incidental pathologic finding when tissue is removed during transurethral resection to manage obstructive symptoms from benign prostatic hyperplasia. Alternatively, patients may present with symptoms of primary or secondary/metastatic disease or due to the generalized effect of malignancy.
Symptoms of the primary disease are, in some cases, attributable to those originating from the prostate volume rather than cancer symptoms per se. These symptoms usually include lower urinary tract symptoms (LUTS), urine retention, and/or hematuria. However, patients with benign prostatic hyperplasia alone can also have similar symptoms.
Symptoms of advanced disease result from any combination of lymphatic, hematogenous, or contiguous local spread. Skeletal manifestations are especially common with more than 70% of people who die of prostate carcinoma having metastatic disease in their bones. Prostate cancer has a strong capability of metastasizing to bone through the hematogenous route, and symptoms will depend on the site of metastasis with manifestation as localized bone pain. The most common bones involved include those of the axial skeleton such as spine and the pelvis, although any bone
may be affected. Beside bones, liver and lungs can also be affected. Lymphatic spread results in lymph node metastasis. Advanced prostate cancer can also be associated with generalized symptoms of malignancy include lethargy, weight loss, and anemia, which may be secondary to marrow infiltration or destruction by metastasis.
In view of the above, early and symptom-independent diagnosis of prostate cancer is highly desirable. As progression of prostate cancer is highly heterogeneous, there remains a need for correct prostate cancer classification which is a critical step in the management of the disease.
The present inventors have identified new biomarkers which allow an improved diagnosis, monitoring, and classification of prostate cancer. They also allow determination of recurrent prostate cancer.
SUMMARY OF THE INVENTION
In a first aspect, the present invention relates to a method of diagnosing prostate cancer in an individual comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eIF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF).
In a second aspect, the present invention relates to a method of determining lymph node involvement in an individual suffering from prostate cancer comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2.
In a third aspect, the present invention relates to a method of determining the course of prostate cancer in an individual comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
In a fourth aspect, the present invention relates to a method of classifying prostate cancer in an individual comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C
(eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
In a fifth aspect, the present invention relates to a method of determining the risk for recurrence/relapse of prostate cancer in an individual comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
In a sixth aspect, the present invention relates to the use of at least one biomarker for diagnosing prostate cancer, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eIF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF).
In a seventh aspect, the present invention relates to the use of at least one biomarker for determining lymph node involvement in an individual suffering from prostate cancer, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2.
In an eight aspect, the present invention relates to the use of at least one biomarker for determining the course of prostate cancer in an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
In a ninth aspect, the present invention relates to the use of at least one biomarker for classifying prostate cancer in an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
In a tenth aspect, the present invention relates to the use of at least one biomarker for determining the risk for recurrence/relapse of prostate cancer in an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
In an eleventh aspect, the present invention relates to a kit comprising means for determining the level of
(i) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eIF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF),
(ii) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2,
(iii) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1),
(iv) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1), and/or
(v) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF), in a biological sample from an individual.
This summary of the invention does not necessarily describe all features of the present invention. Other embodiments will become apparent from a review of the ensuing detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
Preferably, the terms used herein are defined as described in “A multilingual glossary of biotechnological terms: (IUPAC Recommendations)”, Leuenberger, H.G.W, Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, GenBank Accession Number sequence submissions etc.), whether supra or infra, is hereby incorporated by reference in its entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. In the event of a conflict between the definitions or teachings of such incorporated references and definitions or teachings recited in the present specification, the text of the present specification takes precedence.
The term “comprise” or variations such as “comprises” or “comprising” according to the present invention means the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. The term “consisting essentially of’ according to the present invention means the inclusion of a stated integer or group of integers, while excluding modifications or other integers which would materially affect or alter the stated integer. The term “consisting of’ or variations such as “consists of’ according to the present invention means the inclusion of a stated integer or group of integers and the exclusion of any other integer or group of integers.
The terms “a” and “an” and “the” and similar reference used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
The term “and/or” such as “X and/or Y” shall be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning.
The term “prostate cancer”, as used herein, refers to cancer of the prostate. The prostate is a gland in the male reproductive system that surrounds the urethra just below the bladder. Most prostate cancer are slow growing. Cancerous cells may spread to other areas of the body, particularly the bones and lymph nodes. Prostate cancer may initially course no symptoms. In later stages, symptoms include pain or difficulty urinating, blood in the urine, or pain in the pelvis or back. Benign prostatic hyperplasia may produce similar symptoms. Other late symptoms include fatigue, due to low levels of red blood cells. Factors that increase the risk of prostate cancer include older age, family history and race. About 99% of cases occur after age 50. A first-degree relative with the disease increases the risk two- to three-fold. Other factors include a diet high in processed meat and red meat, while the risk from a high intake of milk products is inconclusive. An association with gonorrhoea has been found, although no reason for this relationship has been identified. An increased risk is associated with the BRCA mutations. Diagnosis is by biopsy. Medical imaging may be done to assess whether metastasis is present.
Preferably, prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. More preferably, the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). Even more preferably, the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
The term “diagnosing prostate cancer”, as used herein, means determining whether an individual shows signs of or suffers from prostate cancer.
The term “determining lymph node involvement in an individual suffering from prostate cancer”, as used herein, means determining whether the lymph nodes are affected by the cancer. In this case, prostate cancer cells have spread from the prostate to the lymph nodes. The lymph node involvement (LNI) represents one of the most relevant prognostic factors in prostate cancer patients, where individuals with LNI exhibit an unfavourable natural hi story compared with their counterparts without nodal metastases. The presence of clinical nodal metastases is associated with detrimental oncologic outcomes. Thus, knowing whether lymph nodes are involved in prostate cancer or not is crucial for the determination and selection of treatment options and subsequent therapy.
The term “determining the course of prostate cancer”, as used herein, means evaluating the development of prostate cancer over time, e.g. whether prostate cancer worsens in the individual, does not worsen/is stable in the individual, or improves in the individual over time.
The term “classifying prostate cancer”, as used herein, means determining the stage of prostate cancer. In particular, the classification of prostate cancer allows to determine the size of the cancer and how far it has grown. Knowing the stage helps defining prognosis and is useful when selecting therapies. The most common system is the four-stage TNM system (abbreviated from tumor/nodes/metastases). Its components include the size of the tumor, the number of involved lymph nodes, and the presence of any other metastases. The most important distinction made by any staging system is whether the cancer is confined to the prostate.
The following clinical stages are used to describe prostate cancer:
• Tl: The tumor cannot be felt during digital rectal exam (DRE) or seen during imaging (e.g. a computed tomography (CT) scan or transrectal ultrasound). It may be found when surgery is done for another medical condition. o Tla: The tumor is discovered accidentally during a surgical procedure used to treat benign prostatic hyperplasia (BPH), which is the abnormal growth of benign prostate cells. Cancer is only found in 5 percent or less of the tissue removed.
O Tib: The tumor is found accidentally during BPH surgery. Cancer cells are detected in more than 5 percent of the tissue removed. o Tic: The tumor is found during a needle biopsy that was performed because of an elevated prostate-specific antigen (PSA) level.
• T2: The tumor appears to be confined to the prostate. Due to the size of the tumor, the doctor can feel it during the DRE. The cancer may also be seen with imaging. o T2a: The tumor has invaded one-half (or less) of one side of the prostate. o T2b: The tumor has spread to more than one-half of one side of the prostate, but not to both sides. o T2c: The cancer has invaded both sides of the prostate.
• T3: The tumor has grown outside the prostate. It may have spread to the seminal vesicles. o T3a: The tumor has developed outside the prostate; however, it has not spread to the seminal vesicles. o T3b: The tumor has spread to the seminal vesicles.
• T4: The tumor has spread to tissues next to the prostate other than the seminal vesicles. For example, the cancer may be growing in the rectum, bladder, urethral sphincter (muscle that controls urination) and/or pelvic wall. The lymph nodes may also be affected. Specifically, NO indicates that the tumor has not spread to nearby lymph nodes, while N1 means that it has.
The term “determining the risk for recurrence/relapse of prostate cancer in an individual”, as used herein, means evaluating whether an individual which is in remission (no symptoms or signs of disease) becomes ill again. In other words, the term “determining the risk for recurrence/relapse of prostate cancer in an individual”, as used herein, means evaluating whether prostate cancer comes back (recurred) after an initial treatment. In this case, further treatment can be helpful. The follow-up treatment, however, depends on where the prostate cancer is thought to be and what treatment(s) the individual already had.
After surgery, such as radical prostatectomy, radiation therapy might be an option, sometimes along with hormone therapy. After radiation therapy, for example, treatment options might include cryotherapy or radical prostatectomy, but when these treatments are done after radiation, they carry a higher risk for side effects such as incontinence. Having radiation therapy again is usually not an option because of the increased potential for serious side effects, although in some cases brachytherapy may be an option as a second treatment after external radiation. Another option for some individuals might be active surveillance instead of active treatment. Prostate cancer often grows slowly, so even if it does come back, it might not cause problems for many years, at which time further treatment could then be considered.
The term “individual”, as used herein, refers to any subject for whom it is desired to know whether she or he suffers from prostate cancer. In particular, the term “individual”, as used herein, refers to a subject suspected to be affected by prostate cancer. The individual may be diagnosed to be affected by prostate cancer, i.e. diseased, or may be diagnosed to be not affected by prostate cancer, i.e. healthy. Further, the term “individual”, as used herein, refers to a subject which is affected by prostate cancer, i.e. diseased. The individual may be monitored to determine whether prostate cancer develops over time or not. In particular, the individual may be retested for prostate cancer and may be diagnosed as having developed an advanced form/stage/class of prostate cancer. Furthermore, the term “individual”, as used herein, refers to a subject diagnosed as having prostate cancer with or without lymph node involvement. In addition, the term “individual”, as used herein, refers to a subject suffering from a relapse/recurrence of prostate cancer.
It should be noted that an individual that is diagnosed as being healthy, i.e. not suffering from prostate cancer, may possibly suffer from another disease or condition not tested/known.
The individual may be any mammal, including both a human and another mammal, e.g. an animal such as a rabbit, mouse, rat, or monkey. Human individuals specifically males are particularly preferred.
The term “(control) subject”, as used herein, refers to a subject known to be not affected by prostate cancer (negative control), i.e. healthy. The term “(control) subject”, as used herein, also refers to a subject known to be affected by prostate cancer (positive control), i.e. diseased. Said (control) subject may have developed an advanced form/stage/class of prostate cancer. For example, the (control) subject is a (control) subject with prostate cancer of a specific class (e.g. Tl, T2, T3, or T4, specifically Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, or T4). Further, the term “(control) subject”, as used herein, refers to a subject know to have prostate cancer with or without lymph node involvement. In addition, the term “(control) subject”, as used herein, refers to a successfully treated prostate cancer subject or to a subject known to not experiencing a relapse/recurrence of prostate cancer.
It should be noted that a (control) subject which is known to be healthy, i.e. not suffering from a prostate cancer, may possibly suffer from another disease or condition not tested/known.
The (control) subject may be any mammal, including both a human and another mammal, e.g. an animal such as a rabbit, mouse, rat, or monkey. Human (control) subjects specifically males are particularly preferred.
The term “treatment”, in particular “therapeutic treatment”, as used herein, refers to any therapy which improves the health status and/or prolongs (increases) the lifespan of an individual suffering from a disease or condition, in particular from cancer such as prostate cancer. Said therapy may eliminate the disease or condition in an individual, arrest or slow the development of
a disease in an individual, inhibit or slow the development of a disease in an individual, decrease the frequency or severity of symptoms in an individual, and/or decrease the recurrence in an individual who currently has or who previously has had a disease.
The treatment of a prostate cancer is preferably selected from the group consisting of surgery, chemotherapy, targeted therapy, immunotherapy, oncolytic viral therapy, vaccination therapy, radiotherapy, laser therapy, hyperthermia therapy, cryotherapy, and administration of a drug, or is a combination thereof.
The term “level”, as used herein, refers to an amount (measured for example in grams, mole, or ion counts) or concentration (e.g. absolute or relative concentration) of the at least one biomarker claimed herein. The term “level”, as used herein, also comprises scaled, normalized, or scaled and normalized amounts or values. The level may also be a cut-off level. In one embodiment, the level is an expression level.
The term “eukaryotic Initiation Factor (elF)”, as used herein, refers to a molecule which is involved in the initiation phase of eukaryotic translation. This factor helps to stabilize the formation of the functional ribosome around the start codon and also provides regulatory mechanisms in translation initiation.
In addition, the term “eukaryotic Initiation Factor (elF)”, as used herein, covers elF RNA transcripts (RNA transcript variants) such as mRNAs including splice variants of these transcripts and elF proteins encoded thereby. Thus, the level of the elFs may be determined by measuring mRNA or protein levels. The term “eukaryotic Initiation Factor (elF)”, as used herein, also covers elF isoforms. These elF isoforms are members of a set of highly similar molecules, in particular proteins, that perform the same or similar biological role.
The term “eukaryotic Elongation Factor (eEF)”, as used herein, refers to a molecule that functions at the ribosome during protein synthesis to facilitate translational from the formation of the first to the last peptide bond of a growing polypeptide.
In addition, the term “eukaryotic Elongation Factor (eEF)”, as used herein, covers eEF RNA transcripts (RNA transcript variants) such as mRNAs including splice variants of these transcripts and eEF proteins encoded thereby. Thus, the level of the eEFs may be determined by measuring mRNA or protein levels. The term “eukaryotic Elongation Factor (eEF)”, as used herein, also covers eEF isoforms. These eEF isoforms are members of a set of highly similar molecules, in particular proteins, that perform the same or similar biological role.
The term “Mitochondrial Ribosome Recycling Factor (MRRF)”, as used herein, refers to a molecule which plays essential roles in mitochondrial physiology, including protein synthesis, and it has been implicated in human genetic diseases. The MRRF is among the few protein molecules
that carry their N-terminal signal peptide sequence into the mitochondrial matrix that is required for the interaction of MRRF with the mitoribosome.
The term “ATP-binding cassette sub-family E member 1 (ABCE1)”, as used herein, refers to a molecule which is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the OABP subfamily. Alternatively referred to as the RNase L inhibitor, this protein functions to block the activity of ribonuclease L. Activation of ribonuclease L leads to inhibition of protein synthesis in the 2-5A/RNase L system, the central pathway for viral interferon action.
The term “biological sample”, as used herein, refers to any biological sample from an individual or (control) subject comprising at least one of the biomarkers such as elFs and/or eEFs claimed herein. The biological sample may be a body fluid sample, e.g. a blood sample or urine sample, or a tissue sample. Biological samples may be mixed or pooled, e.g. a sample may be a mixture of a blood sample and a urine sample. Said biological samples may be provided by removing a body fluid from an individual or (control) patient, but may also be provided by using a previously isolated sample. For example, a blood sample may be taken from an individual or (control) subject by conventional blood collection techniques. The biological sample, e.g. urine sample or blood sample, may be obtained from an individual or (control) subject prior to the initiation of a therapeutic treatment, during the therapeutic treatment, and/or after the therapeutic treatment. If the biological sample is obtained from at least one (control) subject, e.g. from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 500, or 1.000 (control) subject(s), it is designated as a “reference biological sample”. Preferably, the reference biological sample is from the same source than the biological sample of the individual to be tested, e.g. both are blood samples or urine samples. It is further preferred that both are from the same species, e.g. from a human. It is also (alternatively or additionally) preferred that the measurements of the reference biological sample and the biological sample of the individual to be tested are identical, e.g. both have an identical volume. It is particularly preferred that the reference biological sample and the biological sample are from individuals/(control) subjects of the same sex and similar age, e.g. no more than 2 years apart from each other.
The term “body fluid sample”, as used herein, refers to any liquid sample derived from the body of an individual or (control) subject containing at least one of the biomarkers such as elFs and/or eEFs claimed herein. Said body fluid sample may be a urine sample, blood sample, sputum sample, breast milk sample, cerebrospinal fluid (CSF) sample, cerumen (earwax) sample, gastric juice sample, mucus sample, lymph sample, endolymph fluid sample, perilymph fluid sample,
peritoneal fluid sample, pleural fluid sample, saliva sample, sebum (skin oil) sample, semen sample, sweat sample, tears sample, cheek swab, vaginal secretion sample, liquid biopsy, or vomit sample including components or fractions thereof. The term “body fluid sample” also encompasses body fluid fractions, e.g. blood fractions, urine fractions or sputum fractions. Body fluid samples may be mixed or pooled. Thus, a body fluid sample may be a mixture of a blood and a urine sample or a mixture of a blood and cerebrospinal fluid sample. Said body fluid sample may be provided by removing a body liquid from an individual or (control) subject, but may also be provided by using previously isolated body fluid sample material. The body fluid sample allows for a non- invasive analysis of an individual or (control) subject. It is further preferred that the body fluid sample has a volume of between 0.01 and 20 ml, more preferably of between 0.1 and 10 ml, even more preferably of between 0.5 and 8 ml, and most preferably of between 1 and 5 ml.
The term “blood sample”, as used herein, encompasses a whole blood sample or a blood fraction sample such as a blood serum or blood plasma sample. It is preferred that the blood serum or plasma sample has a volume of between 0.01 and 20 ml, more preferably of between 0.1 and 10 ml, even more preferably of between 0.5 and 8 ml and most preferably of between 1 and 5 ml.
In the context of the present invention, the term “kit of parts (in short: kit)” is understood to be any combination of at least some of the components identified herein, which are combined, coexisting spatially, to a functional unit, and which can contain further components. Said kit may allow point-of-care testing (POCT).
The term “point-of-care testing (POCT)”, as used herein, refers to a medical diagnostic testing at or near the point of care that is the time and place of individual care. This contrasts with the historical pattern in which testing was wholly or mostly confined to the medical laboratory, which entailed sending off specimens away from the point of care and then waiting hours or days to learn the results, during which time care must continue without the desired information. Point- of-care tests are simple medical tests that can be performed at the bedside. The driving notion behind POCT is to bring the test conveniently and immediately to the individual to be tested. This increases the likelihood that the individual, physician, and care team will receive the results quicker, which allows for immediate clinical management decisions to be made. POCT is often accomplished through the use of transportable, portable, and handheld instruments and test kits. Small bench analyzers or fixed equipment can also be used when a handheld device is not available - the goal is to collect the specimen and obtain the results in a very short period of time at or near the location of the individual so that the treatment plan can be adjusted as necessary before the individual leaves the hospital.
Embodiments of the invention
The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous, unless clearly indicated to the contrary.
Early diagnosis of prostate cancer often increases the likelihood of successful treatment or cure of such disease. The problem is that the majority of prostate cancer patients are asymptomatic. Diagnosis in such cases is based on abnormalities detected by screening for serum levels of prostate-specific antigen (PSA) or findings on digital rectal examination (DRE). In addition, prostate cancer can be an incidental pathologic finding when tissue is removed during transurethral resection to manage obstructive symptoms from benign prostatic hyperplasia. Alternatively, patients may present with symptoms of primary or secondary/metastatic disease or due to the generalized effect of malignancy.
Symptoms of the primary disease are, in some cases, attributable to those originating from the prostate volume rather than cancer symptoms per se. These symptoms usually include lower urinary tract symptoms (LUTS), urine retention, and/or hematuria. However, patients with benign prostatic hyperplasia alone can also have similar symptoms.
Symptoms of advanced disease result from any combination of lymphatic, hematogenous, or contiguous local spread. Skeletal manifestations are especially common with more than 70% of people who die of prostate carcinoma having metastatic disease in their bones. Prostate cancer has a strong capability of metastasizing to bone through the hematogenous route, and symptoms will depend on the site of metastasis with manifestation as localized bone pain. The most common bones involved include those of the axial skeleton such as spine and the pelvis, although any bone may be affected. Beside bones, liver and lungs can also be affected. Lymphatic spread results in lymph node metastasis. Advanced prostate cancer can also be associated with generalized symptoms of malignancy include lethargy, weight loss and anemia, which may be secondary to marrow infiltration or destruction by metastasis.
In view of the above, early and symptom-independent diagnosis of prostate cancer is highly desirable. As progression of prostate cancer is highly heterogeneous, there remains a need for correct prostate cancer classification which is a critical step in the management of the disease.
The present inventors have identified new biomarkers which allow an improved diagnosis, monitoring, and classification of prostate cancer. They also allow determination of recurrent prostate cancer.
The different aspects of the present invention will be further described below:
In a first aspect, the present invention relates to a (an in vitro) method of diagnosing prostate cancer in an individual comprising the step of determining the level of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers) in a biological sample from an individual, wherein the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eIF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF).
In particular, the individual is suspected of having prostate cancer.
For example, the level(s) of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21 biomarker(s), or of 22 biomarkers mentioned above is (are) determined.
In one embodiment, the level of the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers) is compared to a reference level of said at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers). Thus, in one particular embodiment, the present invention relates to a (an in vitro method of diagnosing prostate cancer in an individual comprising the steps of
(i) determining the level of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers) in a biological sample from an individual, and
(ii) comparing the level of the at lest one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers) to a reference level of said at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers), wherein the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eIF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF).
The above comparison allows to diagnose prostate cancer in an individual, in particular in an individual suspected of having prostate cancer. The individual may be diagnosed as suffering from prostate cancer, i.e. being diseased, or as not suffering from prostate cancer, i.e. being healthy.
The reference level may be any level which allows to determine whether an individual suffers from prostate cancer or not. It may be obtained from a (control) subject (i.e. a subject different from the individual to be tested such as a healthy subject and/or a subject known to have prostate cancer) or from the same individual. In the latter case, the individual may be retested for prostate cancer, e.g. in the form of a longitudinal monitoring. It may be determined that the individual is now affected by prostate cancer or still not affected by prostate cancer.
It is preferred that the reference level is the level determined by measuring one or more reference biological sample(s), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 reference biological sample(s), from one or more subject(s) known to be healthy /known to have no prostate cancer, e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 subject(s) known to be healthy/known to have no prostate cancer. Particularly, the reference level is the level determined by measuring between 2 and 500 reference biological samples from between 2 and 500 subjects known to be healthy/known to have no prostate cancer. More particularly, the reference level is determined by measuring between 50 and 500 reference biological samples from between 50 and 500 subjects known to be healthy/known to have no prostate cancer. Even more particularly, the reference level is determined by measuring between 100 and 500 reference biological samples from between 100 and 500 subjects known to be healthy/known to have no prostate cancer.
It is practicable to take one reference biological sample per subject for analysis. If additional reference biological samples are required, e.g. to determine the reference level in different reference biological samples, the same subject may be (re)tested.
Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof.
It is more preferred that
(i) the level of the at least one biomarker selected from the group consisting of eIF4Gl, eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, eIF2Bl, eIF3C, eIF3H, eEFID, eEFIG, eEF2, and MRRF above the reference level indicates that the individual suffers from prostate cancer, and/or
(ii) the level of the at least one biomarker selected from the group consisting of elFl, elFl AX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, and eIF5B below the reference level indicates that the individual suffers from prostate cancer.
It is even more preferred that the level of the at least one biomarker is at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold or 1.5- fold, and most preferably at least 2.0-fold or 3.0-fold below/above the reference level. For example, the level of the at least one biomarker is at least 0.6-fold, at least 0.7-fold, at least 0.8- fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold below/above the reference level.
It is still even more preferred that the level of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6 biomarker(s) or 7 biomarkers) selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, eIF3H, and MRRF is determined. Specific biomarkers selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, and eIF3H or combinations of biomarkers selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, and eIF3H are shown in Figure 19. Optionally, the biomarker is MRRF or MRRF is part of the combinations shown in Figure 19. It is most preferred that the level of at least one biomarker (e.g. 1, 2, 3 biomarker(s) or 4 biomarkers) selected from the group consisting of eIF4Gl, eIF2B5, eIF3B, and MRRF is determined. Specific biomarkers selected from the group consisting of eIF4Gl, eIF2B5, and eIF3B or combinations of biomarkers selected from the group consisting of eIF4Gl, eIF2B5, and eIF3B are shown in Figure 19. Optionally, the biomarker is MRRF or MRRF is part of the combinations shown in Figure 19.
In a second aspect, the present invention relates to a (an in vitro) method of determining lymph node involvement in an individual suffering from prostate cancer comprising the step of: determining the level of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) in a biological sample from an individual, wherein the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2.
In particular, the individual is suspected of having prostate cancer with lymph node involvement or without lymph node involvement.
For example, the level(s) of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8 biomarker(s), or of 9 biomarkers mentioned above is (are) determined.
In one embodiment, the level of the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) is compared to a reference level of said at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers). Thus, in one particular embodiment, the present invention relates to a (an in vitro) method of determining lymph node involvement in an individual suffering from prostate cancer comprising the steps of
(i) determining the level of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) in a biological sample from an individual, and
(ii) comparing the level of the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) to a reference level of said at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers), wherein the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2.
The above comparison allows to determine whether lymph nodes are involved in an individual suffering from prostate cancer or not. If the lymph nodes are involved, prostate cancer cells have spread from the prostate to the lymph nodes. The lymph node involvement (LNI) represents one of the most relevant prognostic factors in prostate cancer patients, where individuals with LNI exhibit an unfavourable natural history compared with their counterparts without nodal metastases. The presence of clinical nodal metastases is associated with detrimental oncologic outcomes. Thus, knowing whether lymph nodes are involved in prostate cancer is crucial for the determination and selection of treatment options and subsequent therapy.
The reference level may be any level which allows to determine whether lymph nodes are involved in an individual suffering from prostate cancer or not.
It is preferred that the reference level is the level determined by measuring one or more reference biological sample(s), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 reference biological sample(s), from one or more subject(s) known to have prostate cancer without lymph node involvement, e.g. from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 subject(s) known to have prostate cancer without lymph node involvement.
Particularly, the reference level is the level determined by measuring between 2 and 500 reference biological samples from between 2 and 500 subjects known to have prostate cancer without lymph node involvement. More particularly, the reference level is determined by measuring between 50
and 500 reference biological samples from between 50 and 500 subjects known to have prostate cancer without lymph node involvement. Even more particularly, the reference level is determined by measuring between 100 and 500 reference biological samples from between 100 and 500 subjects known to have prostate cancer without lymph node involvement.
It is practicable to take one reference biological sample per subject for analysis. If additional reference biological samples are required, e.g. to determine the reference level in different reference biological samples, the same subject may be (re)tested.
Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof. It is more preferred that the level of the at least one biomarker below the reference level (determined by measuring one or more reference biological samples from one or more subjects known to have prostate cancer without lymph node involvement) indicates that the individual suffers from prostate cancer with lymph node involvement.
Alternatively or additionally, the reference level is the level determined by measuring one or more reference biological sample(s), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,
42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 reference biological sample(s), from one or more subject(s) known to have prostate cancer with lymph node involvement, e.g. from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,
48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 subject(s) known to have prostate cancer with lymph node involvement.
Particularly, the reference level is the level determined by measuring between 2 and 500 reference biological samples from between 2 and 500 subjects known to have prostate cancer with lymph node involvement. More particularly, the reference level is determined by measuring between 50 and 500 reference biological samples from between 50 and 500 subjects known to have prostate cancer with lymph node involvement. Even more particularly, the reference level is determined by measuring between 100 and 500 reference biological samples from between 100 and 500 subjects known to have prostate cancer with lymph node involvement.
It is practicable to take one reference biological sample per subject for analysis. If additional reference biological samples are required, e.g. to determine the reference level in different reference biological samples, the same subject may be (re)tested.
Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof.
It is more preferred that the level of the at least one biomarker above the reference level (determined by measuring one or more reference biological samples from one or more subjects known to have prostate cancer with lymph node involvement) indicates that the individual suffers from prostate cancer without lymph node involvement.
It is even more preferred that the level of the at least one biomarker is at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold or 1.5- fold, and most preferably at least 2.0-fold or 3.0-fold below/above the reference level. For example, the level of the at least one biomarker is at least 0.6-fold, at least 0.7-fold, at least 0.8- fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold below/above the reference level.
A prostate cancer without lymph node involvement can also be designated as prostate cancer of NO. A prostate cancer with lymph node involvement can also be designated as prostate cancer of Nl. In this case, prostate cancer is usually prostate cancer of T4.
In a third aspect, the present invention relates to a (an in vitro) method of monitoring/determining the course of prostate cancer in an individual comprising the step of: determining the level of at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) in a biological sample from an individual, wherein the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
In particular, the individual suffers from prostate cancer.
For example, the level(s) of at least 1, at least 2, at least 3, at least 4 biomarker(s), or of 5 biomarkers mentioned above is (are) determined.
In one embodiment, the level of the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) is compared to a reference level of said at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers). Thus, in one particular embodiment, the present invention relates to a (an in vitro) method of monitoring/determining the course of prostate cancer in an individual comprising the steps of
(i) determining the level of at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) in a biological sample from an individual, and
(ii) comparing the level of the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) to a reference level of said at least one biomarker,
wherein the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
The above comparison allows to monitor/determine the course of the prostate cancer in the individual suffering from prostate cancer. It may be determined that prostate cancer worsens in the individual, that prostate cancer does not worsen/is stable in the individual, or that prostate cancer improves in the individual.
The reference level may be any level which allows to monitor/determine the course of the prostate cancer in the individual suffering from prostate cancer. It may be obtained from a (control) subject (i.e. a subject different from the individual to be tested such as a subject known to have prostate cancer).
It is preferred that the reference level is the level determined by measuring one or more reference biological sample(s), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,
44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 reference biological sample(s), from one or more subject(s) known to have prostate cancer, e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 subject(s) known to have prostate cancer. Particularly, the reference level is the level determined by measuring between 2 and 500 reference biological samples from between 2 and 500 subjects known to have prostate cancer. More particularly, the reference level is determined by measuring between 50 and 500 reference biological samples from between 50 and 500 subjects known to have prostate cancer. Even more particularly, the reference level is determined by measuring between 100 and 500 reference biological samples from between 100 and 500 subjects known to have prostate cancer.
The subject(s) known to have prostate cancer may have, for example, prostate cancer of Tl, T2, T3, or T4, specifically Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, or T4.
It is more preferred that the level of the at least one biomarker selected from the group consisting of eIF3C, eIF3H, and ABCE1 above the reference level indicates that prostate cancer progresses/worsens in the individual, and/or the at least one biomarker selected from the group consisting of eIF5A and eIF5B below the reference level indicates that prostate cancer progresses/worsens in the individual.
As already mentioned above, the reference level may be any level which allows to monitor/determine the course of the prostate cancer in the individual suffering from prostate
cancer. It may be obtained from a (control) subject (i.e. a subject different from the individual to be tested such as a subject known to have prostate cancer). It may also be obtained from the same individual.
Thus, in one alternative or additional embodiment, said determining comprises determining the level of the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) in a biological sample from an individual at a first point in time and in at least one further biological sample from the (same) individual at a later point in time and comparing said levels determined at the different time points. Accordingly, in one particular embodiment, the present invention relates to a (an in vitro) method of determining the course of prostate cancer in an individual comprising the steps of
(i) determining the level of the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) in a biological sample from an individual at a first point in time and in at least one further biological sample from the (same) individual at a later point in time, and
(ii) comparing said levels determined at the different time points, wherein the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
This proceeding allows to monitor/determine the course of prostate cancer in an individual having prostate cancer over an extended period of time, such as months or years, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 month(s), 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 year(s).
The above comparison allows to monitor/determine the course of the prostate cancer in the individual suffering from prostate cancer. It may be determined that prostate cancer worsens in the individual, that prostate cancer does not worsen/is stable in the individual, or that prostate cancer improves in the individual.
It is preferred that the level of the at least one biomarker selected from the group consisting of eIF3C, eIF3H, and ABCE1 which
(i) increases over time indicates that prostate cancer progresses/worsens in the individual,
(ii) does not change over time indicates that prostate cancer does not worsen/is stable in the individual, or
(iii) decreases over time indicates that prostate cancer improves in the individual. Specifically, the individual had prostate cancer at the first point in time and the level which increases over time indicates that prostate cancer is worsening in the individual,
the individual had prostate cancer at the first point in time and the level which does not change over time indicates that prostate cancer is not progressing in the individual, or the individual had prostate cancer at the first point in time and the level which decreases over time indicates that prostate cancer is improving in the individual.
It is alternatively or additionally preferred that the level of the at least one biomarker selected from the group consisting of eIF5A and eIF5B which
(i) decreases over time indicates that prostate cancer progresses/worsens in the individual,
(ii) does not change over time indicates that prostate cancer does not worsen/is stable in the individual, or
(iii) increases over time indicates that prostate cancer improves in the individual.
Specifically, the individual had prostate cancer at the first point in time and the level which decreases over time indicates that prostate cancer is worsening in the individual, the individual had prostate cancer at the first point in time and the level which does not change over time indicates that prostate cancer is not progressing in the individual, or the individual had prostate cancer at the first point in time and the level which increases over time indicates that prostate cancer is improving in the individual.]
The increase may be at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1- fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold over time.
The decrease may be at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5- fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold over time.
“Stable”, as mentioned above, means that the level varies over time between 0 and < 20%, e.g. 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 19.9, 19.99, or 19.999%. “Stable” in this respect may also mean that the detected level variation is within the accuracy of a measurement. The accuracy of a measurement depends on the measurement method used. Preferably, the level is constant over time.
The time period between the first point in time and the later point(s) in time preferably amounts to at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6
days, at least 7 days (1 week), at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months (1 year), at least 24 months (2 years), at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, or at least 10 years. For example, the individual may be routinely checked, e.g. once or twice a year. The individual may be (re)tested at 2, 3, 4, 5, 6 7, 8, 9, or 10 time points (first point in time and further point(s) in time).
In addition to the monitoring/determining the course of prostate cancer in an individual, the treatment of this disease can be monitored. In this case, the individual receives, has received, or had received a therapeutic treatment of prostate cancer. The therapeutic treatment of prostate cancer is preferably selected from the group consisting of surgery, chemotherapy, targeted therapy, immunotherapy, oncolytic viral therapy, vaccination therapy, radiotherapy, laser therapy, hyperthermia therapy, cryotherapy, and administration of a drug, or is a combination thereof.
The individual may receive a treatment during the complete monitoring process (e.g. the administration of a drug) or may receive a treatment before, at, or after a first point in time (e.g. the administration of a drug) and may be retested at a later point in time. In particular, said first point in time may be before the initiation of a treatment and said later point in time may be during the treatment and/or after the treatment. If the treatment encompasses the administration of a drug and the individual responds to said treatment, the drug administration may be continued, the dose of the drug may be reduced, or the drug administration may be stopped. If the treatment encompasses the administration of a drug and the individual does not respond to said treatment, the dose of the drug may be increased, the drug may be changed, or the therapy mode may be changed, e.g. from drug administration to surgery or radiotherapy.
Due to the therapeutic treatment, an increased level of the at least one biomarker can be decreased or a decreased level of the at least one biomarker can be increased. In this way, the (overall) condition of the individual having prostate cancer can be improved.
In a fourth aspect, the present invention relates to a method of classifying prostate cancer in an individual comprising the step of determining the level of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers) in a biological sample from an individual, wherein the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
In particular, the individual suffers from prostate cancer.
For example, the level(s) of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18 biomarker(s), or of 19 biomarkers mentioned above is (are) determined.
In one embodiment, the level of the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers) is compared to a reference level of said at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers). Thus, in one particular embodiment, the present invention relates to a (an in vitro) method of classifying prostate cancer in an individual comprising the steps of
(i) determining the level of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers) in a biological sample from an individual, and
(ii) comparing the level of the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers) to a reference level of said at least one biomarker, wherein the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18 biomarker(s), or 19 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
Particularly, the above comparison allows to classify whether the individual suffers from prostate cancer of Tl, T2, T3, or T4. More particularly, the above comparison allows to classify whether the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, or T4.
The reference level may be any level which allows to classify the individual, e.g. as individual suffering from prostate cancer of Tl, T2, T3, or T4, preferably of Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, or T4.
It is preferred that the reference level is the level determined by measuring one or more reference biological sample(s), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 reference biological sample(s),
from one or more subject(s) known to have prostate cancer of Tl, particularly Tla, Tib, and/or Tic, e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 subject(s) known to have prostate cancer of Tl, particularly Tla, Tib, and/or Tic, from one or more subject(s) known to have prostate cancer of T2, particularly T2a, T2b, and/or T2c, e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 subject(s) known to have prostate cancer of T2, particularly T2a, T2b, and/or T2c, from one or more subject(s) known to have prostate cancer of T3, particularly T3a and/or T3b, e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 subject(s) known to have prostate cancer of T3, particularly T3a and/or T3b, and/or from one or more subject(s) known to have prostate cancer of T4 (with lymph node involvement (Nl) or without lymph node involvement (NO)), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 subject(s) known to have prostate cancer of T4 (with lymph node involvement (Nl) or without lymph node involvement (NO)).
Particularly, the reference level is the level determined by measuring between 2 and 500 reference biological samples from between 2 and 500 subjects known to have prostate cancer of Tl, T2, T3, and/or T4, specifically Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, and/or T4. More particularly, the reference level is determined by measuring between 50 and 500 reference biological samples from between 50 and 500 subjects known to have prostate cancer of Tl, T2, T3, and/or T4, specifically Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, and/or T4. Even more particularly, the reference level is determined by measuring between 100 and 500 reference biological samples from between 100 and 500 subjects known to have prostate cancer of Tl, T2, T3, and/or T4, specifically Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, and/or T4.
It is practicable to take one reference biological sample per subject for analysis. If additional reference biological samples are required, e.g. to determine the reference level in different reference biological samples, the same subject may be (re)tested.
Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof.
It is more preferred that
(i) the level of eIF3C above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of eIF3C above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b, or T4, the level of eIF3C above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of T4, the level of eIF3C below the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b, the level of eIF3C below the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 and above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b, the level of eIF3C below the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b and above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, or the level of eIF3C below the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, or T2c,
(ii) the level of eIF3H above the reference level of eIF3H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, the level of eIF3H above the reference level of eIF3H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4,
the level of eIF3H below the reference level of eIF3H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer T la, Tib, Tic, T2a, T2b, or T2c, or T3a, or the level of eIF3H below the reference level of eIF3H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer Tla, Tib, Tic, T2a, or T2b,
(iii) the level of eIF5A below the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, the level of eIF5A below the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of eIF5A below the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b or T4, the level of eIF5A above the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a, the level of eIF5A above the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, or T2c, the level of eIF5A above the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, or T2b, or the level of eIF5A below the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c and above the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of T3a,
(iv) the level of eIF5B below the reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4,
the level of eIF5B below the reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of eIF5B below the reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b or T4, or the level of eIF5B above the reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b and below e reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a,
(v) the level of eIF5 above the reference level of eIF5 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2c, T3a, T3b, or T4, or the level of eIF5 below the reference level of eIF5 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b,
(vi) the level of eIF4H above the reference level of eIF4H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of T4, or the level of eIF4H below the reference level of eIF4H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b,
(vii) the level of eIF3D below the reference level of eIF3D determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or the level of eIF3D above the reference level of eIF3D determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(viii) the level of eIF3G below the reference level of eIF3G determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or
the level of eIF3G above the reference level of eIF3G determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(ix) the level of eIF3L below the reference level of eIF3L determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or the level of eIF3L above the reference level of eIF3L determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(x) the level of eIF3I below the reference level of eIF3I determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, or the level of eIF3I above the reference level of eIF3I determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(xi) the level of eIF3 J below the reference level of eIF3 J determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b or T4, or the level of eIF3 J above the reference level of eIF3 J determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(xii) the level of eIF2B3 below the reference level of eIF2B3 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T3a, T3b, or T4, or the level of eIF2B3 above the reference level of eIF2B3 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(xiii) the level of eEFl Al below the reference level of eEFl Al determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or
the level of eEFl Al above the reference level of eEFl Al determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(xiv) the level of eEF2 below the reference level of eEF2 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or the level of eEF2 above the reference level of eEF2 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(xv) the level of elFl AX above the reference level of elFl AX determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2a, T2c, T3a, T3b, or T4, or the level of elFl AX below the reference level of elFl AX determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b,
(xvi) the level of eIF2Sl above the reference level of eIF2Sl determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2a, T2c, T3a, T3b, or T4, or the level of eIF2Sl below the reference level of eIF2Sl determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b,
(xvii) the level of eIF2B4 below the reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, the level of eIF2B4 below the reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4,
the level of eIF2B4 below the reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b or T4, or the level of eIF2B4 above the reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b and below e reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a,
(xviii) the level of eIF4E above the reference level of eIF4E determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2c, T3a, T3b, or T4, the level of eIF4E above the reference level of eIF4E determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of T4, the level of eIF4E below the reference level of eIF4E determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b, or the level of eIF4E below the reference level of eIF4E determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a, and/or
(xix) the level of ABCE1 above the reference level of ABCE1 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2c, T3a, T3b, or T4, the level of ABCE1 above the reference level of ABCE1 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of ABCE1 below the reference level of ABCE1 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, or T2b, or the level of ABCE1 below the reference level of ABCE1 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b.
In a fifth aspect, the present invention relates to a method of determining the risk for recurrence/relapse of prostate cancer in an individual comprising the step of determining the level of at least one biomarker (e.g. 1 or 2 biomarker(s)) in a biological sample from an individual, wherein the at least one biomarker (e.g. 1 or 2 biomarker(s)) is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
It is preferred that the individual had received a therapeutic treatment of prostate cancer. Specifically, the individual was successfully treated with the therapeutic treatment of prostate cancer.
It is further preferred that the biological sample is isolated after the therapeutic treatment of prostate cancer.
It is more preferred that the therapeutic treatment of the prostate cancer is selected from the group consisting of surgery, chemotherapy, targeted therapy, immunotherapy, oncolytic viral therapy, vaccination therapy, radiotherapy, laser therapy, hyperthermia therapy, cryotherapy, and administration of a drug, or is a combination thereof.
In one embodiment, the level of the at least one biomarker is compared to a reference level of said at least one biomarker. Thus, in one particular embodiment, the present invention relates to a (an in vitro) method of determining the risk for recurrence/relapse of prostate cancer in an individual comprising the steps of
(i) determining the level of at least one biomarker (e.g. 1 or 2 biomarker(s)) in a biological sample from an individual, and
(ii) comparing the level of the at least one biomarker (e.g. 1 or 2 biomarker(s)) to a reference level of said at least one biomarker (e.g. 1 or 2 biomarker(s)), wherein the at least one biomarker (e.g. 1 or 2 biomarker(s)) is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
The above comparison allows to evaluate whether an individual which is in remission (no symptoms or signs of disease) becomes ill again. In other words, the above comparison allows to evaluate whether prostate cancer comes back (recurred) after an initial treatment. In this case, further treatment can be helpful. The follow-up treatment, however, depends on where the prostate cancer is thought to be and what treatment(s) the individual already had.
After surgery, such as radical prostatectomy, radiation therapy might be an option, sometimes along with hormone therapy. After radiation therapy, for example, treatment options might include cryotherapy or radical prostatectomy, but when these treatments are done after radiation, they carry a higher risk for side effects such as incontinence. Having radiation therapy again is usually not
an option because of the increased potential for serious side effects, although in some cases brachytherapy may be an option as a second treatment after external radiation. Another option for some individuals might be active surveillance instead of active treatment. Prostate cancer often grows slowly, so even if it does come back, it might not cause problems for many years, at which time further treatment could then be considered.
The reference level may be any level which allows to determine whether prostate cancer recurred again in the individual. It may be obtained from (control) subjects (i.e. subjects different from the individual to be tested such as healthy subjects or successfully treated prostate cancer subjects/prostate cancer subjects with no recurrence). The reference level may also be obtained from the same individual.
It is preferred that the reference level is the level of the at least one biomarker determined by measuring one or more reference biological sample(s), e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 reference biological sample(s), from one or more healthy subject(s), successfully treated prostate cancer subject(s), or prostate cancer subject(s) with no recurrence, e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 150, 200, 250, 300, 400, 500, or 1.000 healthy subject(s), successfully treated prostate cancer subject(s), or prostate cancer subject(s) with no recurrence. Alternatively, the reference level is from the same individual, e.g. after initial treatment.
It is practicable to take one reference biological sample per subject for analysis. If additional reference biological samples are required, e.g. to determine the reference level in different reference biological samples, the same subject may be (re)tested.
Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof.
It is more preferred that the level of the at least one biomarker above the reference level indicates a risk of the individual for relapse/recurrence of prostate cancer.
It is even more preferred that the level of the at least one biomarker is at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold or 1.5- fold, and most preferably at least 2.0-fold or 3.0-fold above the reference level. For example, the level of the at least one biomarker is at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-
fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold above the reference level.
The individual referred to in the methods of the first to fifth aspect of the present invention may be any mammal, including both a human and another mammal, e.g. an animal such as a rabbit, mouse, rat, or monkey. Human individuals such as males are particularly preferred.
In the methods of the first to fifth aspect of the present invention, it is preferred that the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
In the methods of the first to fifth aspect of the present invention, it is preferred that the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. It is also preferred that the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. Preferably, the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample and a combination thereof. More preferably, the blood sample is a whole blood sample or a blood fraction sample. Even more preferably, the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample. Specifically, the biological sample and the reference biological sample used are identical.
Preferably, the aforementioned samples are pre-treated before they are used in the methods of the first to fifth aspect of the present invention. Said pre-treatment may include treatments required to separate the at least one biomarker described herein, or to remove excessive material or waste. Furthermore, pre-treatments may aim to sterilize samples and/or remove contaminants such as undesired cells, bacteria, or viruses. Suitable techniques comprise centrifugation, extraction, fractioning, ultrafiltration, protein precipitation followed by filtration and purification and/or enrichment of compounds. Moreover, other pre-treatments are carried out in order to provide the at least one biomarker described herein in a form or concentration suitable for analysis.
In one preferred embodiment of the methods of the first to fifth aspect of the present invention, the biological sample used to determine the level of the at least one biomarker is a tissue sample, e.g. tumor tissue sample (obtainable e.g. by biopsy), or a body fluid sample. The biomarkers of the present invention can be found in the tissue affected with the tumor and in body fluids like blood and blood components (e.g. plasma or serum).
According to another preferred embodiment of the methods of first to fifth aspect of the present invention, the level of the at least one biomarker is determined by measuring mRNA or protein levels. The level of the at least one biomarker in the methods of the first to fifth aspect of the present invention can be determined either by measuring a mRNA molecule encoding the at least one biomarker or by measuring the at least one biomarker in protein form. Methods to determine mRNA levels and protein levels in a sample are well known. mRNA expression levels are usually measured by polymerase chain reaction (PCR), in particular by reverse transcription quantitative polymerase chain reaction (RT-PCR and qPCR) or real-time PCR. RT-PCR is used to create a cDNA from the mRNA. The cDNA may be used in a qPCR assay to produce fluorescence as the DNA amplification process progresses. This fluorescence is proportional to the original mRNA amount in the samples. Other methods to be used include Northern blots, Fluorescence in situ hybridization (FISH), microarrays, and RT-PCR combined with capillary electrophoresis. Protein levels of biomarkers are preferably determined using immunoassays. Such methods are based on the binding of an antibody, a derivative or a fragment thereof to its corresponding target (i.e. biomarker). Polyclonal and monoclonal antibodies can be used in such methods. Derivatives or fragments of antibodies include Fab fragments, F(ab')2 fragments, Fv fragments, single chain antibodies and single domain antibodies. Preferred immunoassays include Western blot, Immunohistochemistry, ELISA (enzyme-linked immunosorbent assay), radioimmunoassays, fluorescence resonance energy transfer (FRET) or time resolved-FRET (TR-FRET). It is particularly preferred to use antibodies and derivatives or fragments of antibodies which have been obtained from a non-human source. These antigen binding molecules can be of porcine, rabbit, murine, camel or rat origin. Of course, it is also possible to use antibodies and derivatives or fragments thereof which are recombinantly produced in plants or cell cultures, in particular microbial cell cultures (e.g. bacteria, yeast).
In the methods of the first to fifth aspect of the present invention, it is more preferred that the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
In a sixth aspect, the present invention relates to the (in vitro) use of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers) for diagnosing prostate cancer, wherein the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eIF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF).
Particularly, at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6 biomarker(s) or 7 biomarkers) selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, eIF3H, and MRRF is (are) used for diagnosing prostate cancer. Particularly preferred biomarkers selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, and eIF3H or combinations of biomarkers selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, and eIF3H are shown in Figure 19. Optionally, the biomarker is MRRF or MRRF is part of the combinations shown in Figure 19. More particularly, at least one biomarker (e.g. 1, 2, 3 biomarker(s) or 4 biomarkers) selected from the group consisting of eIF4Gl, eIF2B5, eIF3B, and MRRF is determined. More particularly preferred biomarkers selected from the group consisting of eIF4Gl, eIF2B5, and eIF3B or combinations of biomarkers selected from the group consisting of eIF4Gl, eIF2B5, and eIF3B are shown in Figure 19. Optionally, the biomarker is MRRF or MRRF is part of the combinations shown in Figure 19.
For the above-mentioned use, the level of the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 biomarker(s), or 22 biomarkers) is determined/analyzed in a biological sample from an individual.
It is preferred that the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. It is also preferred that the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. Preferably, the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample, and a combination thereof. More preferably, the blood sample is a whole blood sample or a blood fraction sample. Even more preferably, the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
It is further preferred that the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
It is more preferred that the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
In a seventh aspect, the present invention relates to the (in vitro) use of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) for determining lymph node involvement in an individual suffering from prostate cancer, wherein the at least one
biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2.
For the above-mentioned use, the level of the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8 biomarker(s), or 9 biomarkers) is determined/analyzed in a biological sample from an individual.
It is preferred that the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. It is also preferred that the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. Preferably, the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample, and a combination thereof. More preferably, the blood sample is a whole blood sample or a blood fraction sample. Even more preferably, the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
It is further preferred that the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
It is more preferred that the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
In an eight aspect, the present invention relates to the (in vitro) use of at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) for determining the course of prostate cancer in an individual, wherein the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
For the above-mentioned use, the level of the at least one biomarker (e.g. at least 1, 2, 3, 4 biomarker(s), or 5 biomarkers) is determined/analyzed in a biological sample from an individual.
It is preferred that the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. It is also preferred that the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. Preferably, the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample, and a combination thereof. More preferably, the blood sample is a whole blood sample or a blood
fraction sample. Even more preferably, the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
It is further preferred that the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
It is more preferred that the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
In a ninth aspect, the present invention relates to the (in vitro) use of at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers) for classifying prostate cancer in an individual, wherein the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers) is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
For the above-mentioned use, the level of the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 biomarker(s), or 19 biomarkers) is determined/analyzed in a biological sample from an individual.
It is preferred that the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. It is also preferred that the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. Preferably, the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample, and a combination thereof. More preferably, the blood sample is a whole blood sample or a blood fraction sample. Even more preferably, the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
It is further preferred that the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of
the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
It is more preferred that the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
In a tenth aspect, the present invention relates to the (in vitro) use of at least one biomarker (1 or 2 biomarkers(s)) for determining the risk for recurrence/relapse of prostate cancer in an individual, wherein the at least one biomarker (1 or 2 biomarkers(s)) is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
For the above-mentioned use, the level of the at least one biomarker (e.g. 1 or 2 biomarker(s)) is determined/analyzed in a biological sample from an individual.
It is preferred that the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. It is also preferred that the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. Preferably, the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample, and a combination thereof. More preferably, the blood sample is a whole blood sample or a blood fraction sample. Even more preferably, the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
It is further preferred that the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
It is more preferred that the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
In an eleventh aspect, the present invention relates to a kit comprising means for determining the level of
(i) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eZF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF),
(ii) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2,
(iii) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1),
(iv) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1), and/or
(v) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF), in a biological sample from an individual.
The means for determining the at least one biomarker under (i) are/are used for diagnosing prostate cancer in an individual. In this respect, it is referred to the first aspect of the present invention. Particularly, the at least one biomarker (e.g. at least 1, 2, 3, 4, 5, 6 biomarker(s) or 7 biomarkers) is selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, eIF3H, and MRRF. Particularly preferred biomarkers selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, and eIF3H or combinations of biomarkers selected from the group consisting of eIF4Gl, eIF2Bl, eIF2B5, eIF3B, eIF3C, and eIF3H are shown in Figure 19. Optionally, the biomarker is MRRF or MRRF is part of the combinations shown in Figure 19. More particularly, at least one biomarker (e.g. 1, 2, 3 biomarker(s) or 4 biomarkers) selected from the group consisting of eIF4Gl, eIF2B5, eIF3B, and MRRF is determined. More particularly preferred biomarkers selected from the group consisting of eIF4Gl, eIF2B5, and eIF3B or combinations of biomarkers selected from the group consisting of eIF4Gl, eIF2B5, and eIF3B are shown in Figure 19. Optionally, the biomarker is MRRF or MRRF is part of the combinations shown in Figure 19.
The means for determining the at least one biomarker under (ii) are/are used for determining lymph node involvement in an individual suffering from prostate cancer. In this respect, it is referred to the second aspect of the present invention.
The means for determining the at least one biomarker under (iii) are/are used for determining the course of prostate cancer in an individual. In this respect, it is referred to the third aspect of the present invention.
The means for determining the at least one biomarker under (iv) are/are used for classifying prostate cancer in an individual. In this respect, it is referred to the fourth aspect of the present invention.
The means for determining the at least one biomarker under (iv) are/are used for determining the risk for recurrence/relapse of prostate cancer in an individual. In this respect, it is referred to the fifth aspect of the present invention.
It is preferred that said means may be primers or primer pairs allowing the detection of the above-mentioned biomarker(s) on the RNA transcript, e.g. mRNA, level and/or antibodies, antibody derivatives or fragments of antibodies allowing the detection of the above-mentioned biomarker(s) on the protein level.
In addition, said means encompass dipstrips or dipsticks, e.g. urine or blood dipstrips or dipsticks. Said means are tools used to determine changes in individual’s urine or blood. A dipstrip or dipstick comprises different chemical pads or reagents which react (e.g. change color, in particular by applying an immune assay) when immersed in (e.g. blood or urine), and then removed from the biological sample (e.g. urine or blood sample). The result can be read after a few minutes, preferably after a few seconds.
It is further preferred that the biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. It is also preferred that the reference biological sample is a tissue sample, e.g. tumor tissue sample, or a body fluid sample. Preferably, the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a lymph sample, a saliva sample, and a combination thereof. More preferably, the blood sample is a whole blood sample or a blood fraction sample. Even more preferably, the blood fraction sample is a blood serum sample, a blood plasma sample or a blood cell sample.
It is also preferred that the prostate cancer is selected from the group consisting of adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)), transitional cell carcinoma of the prostate, squamous cell carcinoma of the prostate, small cell prostate cancer, and other rarer types of prostate cancer. It is more preferred that the prostate cancer is adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD)). It is even more preferred that the adenocarcinoma of the prostate is selected from the group consisting of acinar adenocarcinoma of the prostate and ductal adenocarcinoma of the prostate.
It is more preferred that the biological sample is a tissue sample (prostate cancer tissue sample) and the prostate cancer is an adenocarcinoma of the prostate (prostate adenocarcinoma (PRAD).
It is alternatively or additionally preferred that the kit is useful for conducting the methods of the first to fifth aspect of the present invention.
The kit may further comprise
(i) a container, and/or
(ii) a data carrier.
Said data carrier may be a non-electronical data carrier, e.g. a graphical data carrier such as an information leaflet, an information sheet, a bar code or an access code, or an electronical data carrier such as a floppy disk, a compact disk (CD), a digital versatile disk (DVD), a microchip or another semiconductor-based electronical data carrier. The access code may allow the access to a database, e.g. an internet database, a centralized, or a decentralized database. The access code may also allow access to an application software that causes a computer to perform tasks for computer users or a mobile app which is a software designed to run on smartphones and other mobile devices.
Said data carrier may further comprise a reference level of the at least one biomarker referred to herein.
In case that the data carrier comprises an access-code which allows the access to a database, said reference level is deposited in this database.
Moreover, the data carrier may comprise information or instructions on how to carry out the methods according to the first to fifth aspect of the present invention.
Said kit may also comprise materials desirable from a commercial and user standpoint including a buffer(s), a reagent(s) and/or a diluent(s) for determining the level mentioned above.
Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the art in the relevant fields are intended to be covered by the present invention.
BRIEF DESCRIPTION OF THE FIGURES
The following Figures are merely illustrative of the present invention and should not be construed to limit the scope of the invention as indicated by the appended claims in any way.
Figure 1: Shows bar charts of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling
Factor (MRRF) de-regulated between patients suffering from prostate cancer (prostate cancer tissue) and healthy control subjects (non-neoplastic tissue (NNT)).
Figure 2: Shows a histogram combined with a distribution and ROC curves combined with AUCs of eIF2Bl (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF2Bl with a mean area under the curve (AUC) value of 0.805.
Figure 3: Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of eIF2B5 (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF2B5 with a mean area under the curve (AUC) value of 0.807.
Figure 4: Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of eIF3B (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF3B with a mean area under the curve (AUC) value of 0.921.
Figure 5: Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of eIF3C (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF3C with a mean area under the curve (AUC) value of 0.879.
Figure 6: Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of eIF3H (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF3H with a mean area under the curve (AUC) value of 0.928.
Figure 7: Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of eIF4Gl (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF4Gl with a mean area under the curve (AUC) value of 0.848.
Figure 8: Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of MRRF (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of MRRF with a mean area under the curve (AUC) value of 0.930.
Figure 9: Shows bar charts of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2 deregulated between patients suffering from prostate cancer without lymph node involvement (prostate cancer tissue of NO) and prostate cancer with lymph node involvement (prostate cancer tissue of Nl).
Figure 10: Shows bar charts of eukaryotic Initiation Factor 3C (eIF3C), efF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1) de-regulated between different stages of prostate cancer (prostate cancer tissue).
Figure 11: Shows Receiver-Operating-Characteristic (ROC) curve of ABCE1 deregulated between prostate cancer stages T2B and T4 with a mean area under the curve (AUC) value of 0.800.
Figure 12: Shows Receiver-Operating-Characteristic (ROC) curve of elFlAX deregulated between prostate cancer stages T2B and T4 with a mean area under the curve (AUC) value of 0.820.
Figure 13: Shows Receiver-Operating-Characteristic (ROC) curve of eIF12Sl deregulated between prostate cancer stages T2B and T4 with a mean area under the curve (AUC) value of 0.800.
Figure 14: Shows Receiver-Operating-Characteristic (ROC) curve of eIF5 de-regulated between prostate cancer stages T2B and T4 with a mean area under the curve (AUC) value of 0.850.
Figure 15: Shows bar charts with arithmetic means and standard deviation of eIF4Gl with no recurrence combined with high grade versus recurrence combined with high grade, and no recurrence and T3 or T4 versus recurrence and T3 or T4. High grade is defined as either (i) a primary Gleason Score of 3 and a secondary Gleason Score of 4 and a tertiary Gleason Score of 5, or (ii) a primary Gleason Score of 4, or (iii) a primary Gleason Score of 5.
Figure 16: Shows bar charts with arithmetic means and standard deviation of MRRF with no recurrence combined with high grade versus recurrence combined with high grade, and no recurrence and T3 or T4 versus recurrence and T3 or T4, and no recurrence combined with the stage NO and high grade versus recurrence combined with NO and high grade.
Figure 17: Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of eIF4Gl with recurrence (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF4Gl with a mean area under the curve (AUC) value of 0.865.
Figure 18: Shows a histogram combined with a distribution and ROC curves combined with AUCs diagrams of MRRF with recurrence (using quickscore) in prostate cancer tissue compared to non-neoplastic tissue (NNT) and Receiver-Operating-Characteristic (ROC) curve of eIF4Gl with a mean area under the curve (AUC) value of 0.853.
Figure 19: Preferred biomarkers selected from the group consisting of eIF2Bl, eIF2B5, eIF3B, eIF3C, eIF3H, and eIF4Gl or combinations (signatures) of biomarkers selected from the group consisting of eIF2Bl, eIF2B5, eIF3B, eIF3C, eIF3H, and eIF4Gl. Optionally, the biomarker is MRRF or MRRF is part of the combinations.
EXAMPLES
The examples given below are for illustrative purposes only and do not limit the invention described above in any way.
Materials
The TCGA PRAD (Prostate Adenocarcinoma) gene expression dataset (from https://gdac.broadinstitute.org) was used including different types of prostate tissues with clinical information about the patients (healthy cohort and cancer cohort) like Gleason score (primary, secondary, tertiary), subtype, T, N, M stages.
The expression diverse biomarkers such as Initiation and Elongation Translation Factors as well as Recycling and Termination Factors were analyzed.
Tissue Micro Arrays (TMAs) of prostate cancer tissue and non-neoplastic tissue (NNT) were immunohistochemically (antibody) treated against the translation factors. Based on the density * intensity scores (quickscores) were calculated.
Methods
The expression diverse biomarkers such as Initiation and Elongation Translation Factors as well as Recycling and Termination Factors were analyzed between healthy subjects and patients suffering from prostate cancer and based on different stagings between and also within the patient groups using Wilcoxon p-Values in combination with the average mean expression of a group.
With Pearson for metric data correlations between each gene from each group were performed. With Spearman for ordinal data correlations between each gene from each group were performed. Wilcoxon test was used to compare the mean of the gene expressions of each group to each other. This is recommended for independent samples.
A p value <0.05 was considered as statistically significant. Statistical analysis was performed with the common R library and was called from C# by using the R.NET package. Graph generation was performed using Microsoft Word and Excel. Graphs and diagrams were created with the common R library.
Histograms with distributions of the quickscores were created based on PRAD tissues and non-neoplastic tissues.
For the AUCs and the ROC curves, a generalized linear model was used considering a score below or equal to 8 as true negative if it was based on NNT and a score of 9 or more as true positive if the quickscore was calculated based on a tumor spot for each translation factor. If the quickscore was at least 9 and it was a NNT it was considered as false negative for each translation factor and if the quickscore was lower or equal to 8 in cancer tissue it was considered as false positive. Results
Reduced significant translation factors (Wilcoxon p < 0.05) by drawing genes randomly from two different groups each, pooled together with the lowest p-value and the lowest number of genes.
Claims
CLAIMS A method of diagnosing prostate cancer in an individual comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eIF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF). The method of claim 1, wherein the level of the at least one biomarker is compared to a reference level of said at least one biomarker. The method of claim 2, wherein the reference level is the level determined by measuring one or more reference biological samples from one or more subjects known to be healthy. The method of claim 3, wherein
(i) the level of the at least one biomarker selected from the group consisting of eIF4Gl, eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, eIF2Bl, eIF3C, eIF3H, eEFID, eEFIG, eEF2, and MRRF above the reference level indicates that the individual suffers from prostate cancer, and/or
(ii) the level of the at least one biomarker selected from the group consisting of elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, and eIF5B below the reference level indicates that the individual suffers from prostate cancer. A method of determining lymph node involvement in an individual suffering from prostate cancer comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2. The method of claim 5, wherein the level of the at least one biomarker is compared to a reference level of said at least one biomarker.
7. The method of claim 6, wherein the reference level is the level determined by measuring one or more reference biological samples from one or more subjects known to have prostate cancer without lymph node involvement.
8. The method of claim 7, wherein the level of the at least one biomarker below the reference level indicates that the individual suffers from prostate cancer with lymph node involvement.
9. A method of determining the course of prostate cancer in an individual comprising the step of determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
10. The method of claim 9, wherein the level of the at least one biomarker is compared to a reference level of said at least one biomarker.
11. The method of claim 10, wherein the reference level is the level determined by measuring one or more reference biological samples from one or more subjects known to have prostate cancer.
12. The method of claim 11, wherein the level of the at least one biomarker selected from the group consisting of eIF3C, efF3H, and ABCE1 above the reference level indicates that prostate cancer progresses/worsens in the individual, and/or the at least one biomarker selected from the group consisting of eIF5A and eIF5B below the reference level indicates that prostate cancer progresses/worsens in the individual.
13. The method of any one of claims 9 to 12, wherein said determining comprises determining the level of the at least one biomarker in a biological sample from an individual at a first point in time and in at least one further biological sample from the (same) individual at a later point in time and comparing said levels determined at the different time points.
14. The method of claim 13, wherein the level of the at least one biomarker selected from the group consisting of eIF3C, eIF3H, and ABCE1 which
(i) increases over time indicates that prostate cancer progresses/worsens in the individual,
(ii) does not change over time indicates that prostate cancer does not worsen/is stable in the individual, or
(iii) decreases over time indicates that prostate cancer improves in the individual.
15. The method of claims 13 or 14, wherein the level of the at least one biomarker selected from the group consisting of eIF5A and eIF5B which
(i) decreases over time indicates that prostate cancer progresses/worsens in the individual,
(ii) does not change over time indicates that prostate cancer does not worsen/is stable in the individual, or
(iii) increases over time indicates that prostate cancer improves in the individual.
16. The method of any one of claims 9 to 15, wherein the individual receives, has received, or had received a therapeutic treatment of prostate cancer.
17. The method of claim 16, wherein the therapeutic treatment of the prostate cancer is selected from the group consisting of surgery, chemotherapy, targeted therapy, immunotherapy, oncolytic viral therapy, vaccination therapy, radiotherapy, laser therapy, hyperthermia therapy, cryotherapy, and administration of a drug, or is a combination thereof.
18. A method of classifying prostate cancer in an individual comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
19. The method of claim 18, wherein the level of the at least one biomarker is compared to a reference level of said at least one biomarker.
The method of claim 19, wherein the reference level is the level determined by measuring one or more reference biological samples from one or more subjects known to have prostate cancer of Tl, T2, T3, and/or T4, preferably Tla, Tib, Tic, T2a, T2b, T2c, T3a, T3b, and/or T4. The method of claim 20, wherein
(i) the level of eIF3C above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of eIF3C above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b, or T4, the level of eIF3C above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of T4, the level of eIF3C below the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b, the level of eIF3C below the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 and above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b, the level of eIF3C below the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b and above the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, or the level of eIF3C below the reference level of eIF3C determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, or T2c,
(ii) the level of eIF3H above the reference level of eIF3H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, the level of eIF3H above the reference level of eIF3H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of eIF3H below the reference level of eIF3H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer Tla, Tib, Tic, T2a, T2b, or T2c, or T3a, or the level of eIF3H below the reference level of eIF3H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer Tla, Tib, Tic, T2a, or T2b,
(iii) the level of eIF5A below the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, the level of eIF5A below the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of eIF5A below the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b or T4, the level of eIF5A above the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a, the level of eIF5A above the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate
cancer of T3a indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, or T2c, the level of eIF5A above the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, or T2b, or the level of eIF5A below the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c and above the reference level of eIF5A determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of T3a,
(iv) the level of eIF5B below the reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, the level of eIF5B below the reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of eIF5B below the reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b or T4, or the level of eIF5B above the reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b and below e reference level of eIF5B determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a,
(v) the level of eIF5 above the reference level of eIF5 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2c, T3a, T3b, or T4, or the level of eIF5 below the reference level of eIF5 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer
of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b,
(vi) the level of eIF4H above the reference level of eIF4H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of T4, or the level of eIF4H below the reference level of eIF4H determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b,
(vii) the level of eIF3D below the reference level of eIF3D determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or the level of eIF3D above the reference level of eIF3D determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(viii) the level of eIF3G below the reference level of eIF3G determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or the level of eIF3G above the reference level of eIF3G determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(ix) the level of eIF3L below the reference level of eIF3L determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or the level of eIF3L above the reference level of eIF3L determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(x) the level of eIF3I below the reference level of eIF3I determined by measuring one or more reference biological samples from one or more subjects having prostate
cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, or the level of eIF3I above the reference level of eIF3I determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(xi) the level of eIF3 J below the reference level of eIF3 J determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b or T4, or the level of eIF3 J above the reference level of eIF3 J determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(xii) the level of eIF2B3 below the reference level of eIF2B3 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T3a, T3b, or T4, or the level of eIF2B3 above the reference level of eIF2B3 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(xiii) the level of eEFl Al below the reference level of eEFl Al determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or the level of eEFlAl above the reference level of eEFlAl determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(xiv) the level of eEF2 below the reference level of eEF2 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, or
the level of eEF2 above the reference level of eEF2 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a,
(xv) the level of elFlAX above the reference level of elFlAX determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2a, T2c, T3a, T3b, or T4, or the level of elFlAX below the reference level of elFlAX determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b,
(xvi) the level of eIF2Sl above the reference level of eIF2Sl determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2a, T2c, T3a, T3b, or T4, or the level of eIF2Sl below the reference level of eIF2Sl determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b,
(xvii) the level of eIF2B4 below the reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2a indicates that the individual suffers from prostate cancer of T2b, T2c, T3a, T3b, or T4, the level of eIF2B4 below the reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of eIF2B4 below the reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3a indicates that the individual suffers from prostate cancer of T3b or T4, or the level of eIF2B4 above the reference level of eIF2B4 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b and below e reference level of eIF2B4 determined by measuring one
or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, (xviii) the level of eIF4E above the reference level of eIF4E determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2c, T3a, T3b, or T4, the level of eIF4E above the reference level of eIF4E determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of T4, the level of eIF4E below the reference level of eIF4E determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b, or the level of eIF4E below the reference level of eIF4E determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T3b indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, or T3a, and/or
(xix) the level of ABCE1 above the reference level of ABCE1 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2b indicates that the individual suffers from prostate cancer of T2c, T3a, T3b, or T4, the level of ABCE1 above the reference level of ABCE1 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of T3a, T3b, or T4, the level of ABCE1 below the reference level of ABCE1 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T2c indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, or T2b, or the level of ABCE1 below the reference level of ABCE1 determined by measuring one or more reference biological samples from one or more subjects having prostate cancer of T4 indicates that the individual suffers from prostate cancer of Tla, Tib, Tic, T2a, T2b, T2c, T3a, or T3b.
22. A method of determining the risk for recurrence/relapse of prostate cancer in an individual comprising the step of: determining the level of at least one biomarker in a biological sample from an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
23. The method of claim 22, wherein the individual had received a therapeutic treatment of prostate cancer.
24. The method of claims 22 or 23, wherein the biological sample is isolated after the therapeutic treatment of prostate cancer.
25. The method of claims 23 or 24, wherein the therapeutic treatment of the prostate cancer is selected from the group consisting of surgery, chemotherapy, targeted therapy, immunotherapy, oncolytic viral therapy, vaccination therapy, radiotherapy, laser therapy, hyperthermia therapy, cryotherapy, and administration of a drug, or is a combination thereof.
26. The method of any one of claims 22 to 25, wherein the level of the at least one biomarker is compared to a reference level of said at least one biomarker.
27. The method of claim 26, wherein the reference level is the level of the at least one biomarker determined by measuring one or more reference biological samples from one or more successfully treated prostate cancer subjects/prostate cancer subjects with no recurrence.
28. The method of claim 27, wherein the level of the at least one biomarker above the reference level indicates a risk of the individual for relapse/recurrence of prostate cancer.
29. The method of any one of claims 1 to 28, wherein the biological sample is a tumor tissue sample or a body fluid sample.
30. The method of claim 29, wherein the body fluid sample is a blood, lymph, or saliva sample.
31. The method of claim 30, wherein the blood sample is whole blood sample or a blood fraction, preferably serum, plasma or blood cells.
32. The method of any one of claims 1 to 31, wherein the level of the at least one biomarker is determined by measuring mRNA or protein levels.
33. The method of any one of claims 1 to 32, wherein the individual is a human.
34. Use of at least one biomarker for diagnosing prostate cancer, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eIF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF).
35. Use of at least one biomarker for determining lymph node involvement in an individual suffering from prostate cancer, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2.
36. Use of at least one biomarker for determining the course of prostate cancer in an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
37. Use of at least one biomarker for classifying prostate cancer in an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1).
38. Use of at least one biomarker for determining the risk for recurrence/relapse of prostate cancer in an individual, wherein the at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF).
A kit comprising means for determining the level of
(i) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl), eIF2B4, eIF2B5, eIF2S3, eIF3B, eIF3I, eIF3M, elFl, elFlAX, eIF2B2, eIF2Sl, eIF4E, eIF4H, eIF5, eIF5B, eIF2Bl, eIF3C, eIF3H, eukaryotic Elongation Factor ID (eEFID), eEFIG, eEF2, and Mitochondrial Ribosome Recycling Factor (MRRF),
(ii) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3D (eIF3D), eIF3L, eIF3M, eIF4B, eIF5A, eIF5B, eukaryotic Elongation Factor 1A1 (eEFlAl), eEFlB2, and eEF2,
(iii) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF5A, eIF3H, eIF5B, and ATP Binding Cassette Subfamily E Member 1 (ABCE1),
(iv) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 3C (eIF3C), eIF3H, eIF5A, eIF5B, eIF5, eIF4H, eIF3D, eIF3G, eIF3L, eIF3I, eIF3J, eIF2B3, eIF2Sl, elFlAX, eIF2B4, eIF4E, eukaryotic Elongation Factor 1A1 (eEFlAl), eEF2, and ATP Binding Cassette Subfamily E Member 1 (ABCE1), and/or
(v) at least one biomarker is selected from the group consisting of eukaryotic Initiation Factor 4G1 (eIF4Gl) and Mitochondrial Ribosome Recycling Factor (MRRF), in a biological sample from an individual. The kit of claim 39, wherein the kit is useful for conducting the methods according to any one of claims 1 to 33. The kit of claims 39 or 40, wherein the kit further comprises
(i) a container, and/or
(ii) a data carrier. The kit of claim 41, wherein the data carrier comprises instructions on how to carry out the methods according to any one of claims 1 to 33.
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US20160025733A1 (en) * | 2013-03-09 | 2016-01-28 | Harry Stylli | Methods of detecting prostate cancer |
US20160299145A1 (en) * | 2006-11-13 | 2016-10-13 | Life Technologies Corporation | Methods and Kits for Detecting Prostate Cancer Biomarkers |
US20190094228A1 (en) * | 2016-03-04 | 2019-03-28 | Ait Austrian Institute Of Technology Gmbh | Prostate cancer diagnostic method and means |
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US20160299145A1 (en) * | 2006-11-13 | 2016-10-13 | Life Technologies Corporation | Methods and Kits for Detecting Prostate Cancer Biomarkers |
US20160025733A1 (en) * | 2013-03-09 | 2016-01-28 | Harry Stylli | Methods of detecting prostate cancer |
US20190094228A1 (en) * | 2016-03-04 | 2019-03-28 | Ait Austrian Institute Of Technology Gmbh | Prostate cancer diagnostic method and means |
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