EP1131095A1 - Methode permettant de diagnostiquer, de surveiller, de classer par stades, de visualiser et de traiter le cancer de la prostate - Google Patents

Methode permettant de diagnostiquer, de surveiller, de classer par stades, de visualiser et de traiter le cancer de la prostate

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Publication number
EP1131095A1
EP1131095A1 EP99955004A EP99955004A EP1131095A1 EP 1131095 A1 EP1131095 A1 EP 1131095A1 EP 99955004 A EP99955004 A EP 99955004A EP 99955004 A EP99955004 A EP 99955004A EP 1131095 A1 EP1131095 A1 EP 1131095A1
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European Patent Office
Prior art keywords
csg
levels
patient
cancer
prostate cancer
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EP99955004A
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German (de)
English (en)
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EP1131095A4 (fr
Inventor
Susana Salceda
Herve Recipon
Robert Cafferkey
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Diadexus Inc
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Diadexus Inc
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Publication of EP1131095A1 publication Critical patent/EP1131095A1/fr
Publication of EP1131095A4 publication Critical patent/EP1131095A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer

Definitions

  • This invention relates, in part, to newly developed assays for detecting, diagnosing, monitoring, staging, prognosticating, imaging and treating cancers, particularly prostate cancer.
  • Cancer of the prostate is the most prevalent malignancy in adult males, excluding skin cancer, and is an increasingly prevalent health problem in the United States. In 1996, it was estimated that 41,400 deaths would result from this disease in the United States alone, indicating that prostate cancer is second only to lung cancer as the most common cause of death in the same population. If diagnosed and treated early, when the cancer is still confined to the prostate, the chances of cure is significantly higher.
  • AUA American Urological Association
  • the AUA system divides prostate tumors into four stages, A to D. Stage A, microscopic cancer within prostate, is further subdivided into stages Al and A2.
  • Stage Al is a well-differentiated cancer confined to one site within the prostate. Treatment is generally observation, radical prostatectomy, or radiation.
  • Sub-stage A2 is a moderately to poorly differentiated cancer at multiple sites within the prostate. Treatment is radical prostatectomy or radiation.
  • Stage B palpable lump within the prostate, is also further subdivided into sub-stages Bl and B2.
  • sub-stage Bl the cancer forms a small nodule in one lobe of the prostate.
  • the cancer forms large or multiple nodules, or occurs in both lobes of tfre prostate.
  • Treatment for sub-stages Bl and B2 is either radical prostatectomy or radiation.
  • Stage C is a large cancer mass involving most or all of the prostate and is also further subdivided into two sub-stages.
  • the cancer forms a continuous mass that may have extended beyond the prostate.
  • sub-stage C2 the cancer forms a continuous mass that invades the surrounding tissue.
  • Treatment for both these sub-stages is radiation with or without drugs to address the cancer.
  • Stage D is metastatic cancer and is also subdivided into two sub-stages.
  • sub-stage Dl the cancer appears in the lymph nodes of the pelvis.
  • sub-stage D2 the cancer involves tissues beyond lymph nodes. Treatment for both of these sub-stages is systemic drugs to address the cancer as well as pain.
  • cancer specific genes or CSGs include, but are not limited to: Prol09 which is a human zinc- ⁇ 2-glycoprotein (Freje et al. Genomics 1993 18 (3) : 575-587 ) ; Proll2 which is a human cysteine-rich protein with a zinc-finger motif (Liebhaber et al. Nucleic Acid Research 1990 18 (13) : 3871-3879; W ⁇ 9514772 and 09845436) ; Prolll which is a prostate-specific transglutaminase (Dubbink et al .
  • Genomics 1998 51 (3) : 434-44 Proll5 which is a novel serine protease with transmembrane, LDLR, and SRCR domains and maps to 21q22.3 (Paoloni-Giacobino et al. Genomics 1997 44 (3) : 309-320; 09837418 and O987093); ProllO which is a human breast carcinoma fatty acid synthase (U.S. Patent 5,665,874 and WO9403599) ; Proll3 which is a homeobox gene, HOXB13 (Steinicki et al. J. Invest. Dermatol.
  • ESTs for these CSGs are set forth in SEQ ID NO: 1, 3, 5, 7, 9, 11, 13 and 15 while the full length contigs for these CSGs are set forth in SEQ ID NO:2, 4, 6, 8, 10, 12, 14 and 16, respectively. Additional CSGs for use in the present invention are depicted herein in SEQ ID NO: 17, 18, 19 and 20.
  • methods are provided for detecting, diagnosing, monitoring, staging, prognosticating, imaging and treating prostate cancer via the cancer specific genes referred to herein as CSGs.
  • CSG refers, among other things, to native protein expressed by the gene comprising a polynucleotide sequence of SEQ ID NO:l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • CSG it is also meant herein polynucleotides which, due to degeneracy in genetic coding, comprise variations in nucleotide sequence as compared to SEQ ID NO: 1-20, but which still encode the same protein.
  • CSG means the native mRNA encoded by the gene comprising the polynucleotide sequence of SEQ ID N0:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, levels of the gene comprising the polynucleotide sequence of SEQ ID NO:l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or levels of a polynucleotide which is capable of hybridizing under stringent conditions to the antisense sequence of SEQ ID NO:l, 2, 3, 4, 5, 6, 7, 8, 9, 40, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • a method of diagnosing metastatic prostate cancer in a patient having prostate cancer which is not known to have metastasized by identifying a human patient suspected of having prostate cancer that has metastasized; analyzing a sample of cells, tissues, or bodily fluid from such patient for CSG; comparing the CSG levels in such cells, tissues, or bodily fluid with levels of CSG in preferably the same cells, tissues, or bodily fluid type of a normal human control, wherein an increase in CSG levels in the patient versus the normal human control is associated with prostate cancer which has metastasized.
  • Also provided by the invention is a method of staging prostate cancer in a human which has such * cancer by identifying a human patient having such cancer; analyzing a sample of cells, tissues, or bodily fluid from such patient for CSG; comparing CSG levels in such cells, tissues, or bodily fluid with levels of CSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in CSG levels in the patient versus the normal human control is associated with a cancer which is progressing and a decrease in the levels of CSG is associated with a cancer which is regressing or in remission.
  • the method comprises identifying a human patient having such cancer that is not known to have metastasized; periodically analyzing a sample of cells, tissues, or bodily fluid from such patient for CSG; comparing the CSG levels in such cells, tissue, or bodily fluid with levels of CSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in CSG levels in the patient versus the normal human control is associated with a cancer which has metastasized.
  • the method comprises identifying a human patient having such cancer; periodically analyzing a sample of cells, tissues, or bodily fluid from such patient for CSG; comparing the CSG levels in such cells, tissue, or bodily fluid with levels of CSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in CSG levels in the patient versus the normal human control is associated with a cancer which is progressing and a decrease in the levels of CSG is associated with a cancer which is regressing or in remission.
  • therapeutic agents such as antibodies targeted against CSG or fragments of such antibodies can be used to detect or image localization of CSG in a patient for the purpose of detecting or diagnosing a disease or condition.
  • Such antibodies can be polyclonal, monoclonal, or omniclonal or prepared by molecular biology techniques.
  • the term "antibody”, as used herein and throughout the instant specification is also meant to include aptamers and single-stranded oligonucleotides such as those derived from an in vi tro evolution protocol referred to as SELEX and well known to those skilled in the art.
  • Antibodies can be labeled with a variety of detectable labels including, but not limited to, radioisotopes and paramagnetic metals. Therapeutics agents such as antibodies or fragments thereof can also be used in the treatment of diseases characterized by expression of CSG. In these applications, the antibody can be used without or with derivatization to a cytotoxic agent such as a radioisotope, enzyme, toxin, drug or a prodrug.
  • a cytotoxic agent such as a radioisotope, enzyme, toxin, drug or a prodrug.
  • the present invention relates to diagnostic assays and methods, both quantitative and qualitative for detecting, diagnosing, monitoring, staging and prognosticating cancers by comparing levels of CSG in a human patient with those of CSG in a normal human control.
  • CSG levels is, among other things, native protein expressed by the gene comprising a polynucleotide sequence of SEQ ID NO:l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • CSG it is also meant herein polynucleotides which, due to degeneracy in genetic coding, comprise variations in nucleotide sequence as compared to SEQ ID NO: 1-20, but which still encode the same protein.
  • the native protein being detected may be whole, a breakdown product, a complex of molecules or chemically modified.
  • CSG means the native mRNA encoded by the gene comprising the polynucleotide sequence of SEQ ID NO:l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, levels of the gene comprising the polynucleotide sequence of SEQ ID NO:l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or levels of a polynucleotide which is capable of hybridizing under stringent conditions to the antisense sequence of SEQ ID NO:l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • Such levels are preferably determined in at least one of, cells, tissues and/or bodily fluids, including determination of normal and abnormal levels.
  • a diagnostic assay in accordance with the invention for diagnosing overexpression of CSG protein compared to normal control bodily fluids, cells, or tissue samples may be used to diagnose the presence of prostate cancer.
  • All the methods of the present invention may optionally include determining the levels of other cancer markers as well as CSG.
  • Other cancer markers, in addition to CSG, useful in the present invention will depend on the cancer being tested and are known to those of skill in the art. Diagnostic Assays
  • the present invention provides methods for diagnosing the presence of prostate cancer by analyzing for changes in levels of CSG in cells, tissues or bodily fluids compared with levels of CSG in cells, tissues or bodily fluids of preferably the same type from a normal human control, wherein an increase in levels of CSG in the patient versus the normal human control is associated with the presence of prostate cancer.
  • a positive result indicating the patient being tested has cancer is one in which cells, tissues or bodily fluid levels of the cancer marker, such as CSG, are at least two times higher, and most preferably are at least five times higher, than in preferably the same cells, tissues or bodily fluid of a normal human control.
  • the cancer marker such as CSG
  • the present invention also provides a method of diagnosing metastatic prostate cancer in a patient having prostate cancer which has not yet metastasized for the onset of metastasis.
  • a human cancer patient suspected of having prostate cancer which may have metastasized (but which was not previously known to have metastasized) is identified. This is accomplished by a variety of means known to those of skill in the art.
  • determining the presence of CSG levels in cells, tissues or bodily fluid is particularly useful for discriminating between prostate cancer which has not metastasized and prostate cancer which has metastasized.
  • Existing techniques have difficulty discriminating between prostate cancer which has metastasized and prostate cancer which has not metastasized and proper treatment selection is often dependent upon such knowledge.
  • the cancer marker levels measured in such cells, tissues or bodily fluid is CSG, and are compared with levels of CSG in preferably the same cells, tissue or bodily fluid type of a normal human control. That is, if the cancer marker being observed is just CSG in serum, this level is preferably compared with the levef of CSG in serum of a normal human control. An increase in the CSG in the patient versus the normal human control is associated with prostate cancer which has metastasized.
  • a positive result indicating the cancer in the patient being tested or monitored has metastasized is one in which cells, tissues or bodily fluid levels of the cancer marker, such as CSG, are at least two times higher, and most preferably are at least five times higher, than in preferably the same cells, tissues or bodily fluid of a normal patient.
  • the cancer marker such as CSG
  • Normal human control as used herein includes a human patient without cancer and/or non cancerous samples from the patient; in the methods for diagnosing or monitoring for metastasis, normal human control may preferably also include samples from a human patient that is determined by reliable methods to have prostate cancer which has not metastasized. Staging
  • the invention also provides a method of staging prostate cancer in a human patient.
  • the method comprises identifying a human patient having such cancer and analyzing cells, tissues or bodily fluid from such human patient for CSG.
  • the CSG levels determined in the patient are then compared with levels of CSG in preferably the same cells, tissues or bodily fluid type of a normal human control, wherein an increase in CSG levels in the human patient versus the normal human control is associated with a cancer which is progressing and a decrease in the levels of CSG (but still increased over true normal levels) is associated with a cancer which is regressing or in remission.
  • the method comprises identifying a human patient having such cancer that is not known to have me*tastas ⁇ zed; periodically analyzing cells, tissues or bodily fluid from such human patient for CSG; and comparing the CSG levels determined in the human patient with levels of CSG in preferably the same cells, tissues or bodily fluid type of a normal human control, wherein an increase in CSG levels in the human patient versus the normal human control is associated with a cancer which has metastasized.
  • normal human control samples may also include prior patient samples.
  • the method comprises identifying a human patient having such cancer; periodically analyzing cells, tissues or bodily fluid from such human patient for CSG; and comparing the CSG levels determined in the human patient with levels of CSG in preferably the same cells, tissues or bodily fluid type of a normal human control, wherein an increase in CSG levels in the human patient versus the normal human control is associated with a cancer which is progressing in stage and a decrease in the levels of CSG is associated with a cancer which is regressing in stage or in remission.
  • normal human control samples may also include prior patient samples.
  • Assay Techniques Assay techniques that can be used to determine levels of gene expression (including protein levels) , such as CSG of the present invention, in a sample derived from a patient are well known to those of skill in the art.
  • Such assay methods include, without limitation, radioimmunoassays, reverse transc ⁇ ptase PCR (RT-PCR) assays, lmmunohistochemistry assays, in situ hybridization assays, competitive-binding assays, Western Blot analyses, ELISA assays affd proteomic approaches: two-dimensional gel electrophoresis (2D electrophoresis ) and non-gel based approaches such as mass spectrometry or protein interaction profiling. Among these, ELISAs are frequently preferred to diagnose a gene's expressed protein in biological fluids .
  • RT-PCR reverse transc ⁇ ptase PCR
  • lmmunohistochemistry assays in situ hybridization assays
  • competitive-binding assays Western Blot analyses
  • ELISA assays affd proteomic approaches: two-dimensional gel electrophoresis (2D electrophoresis ) and non-gel based approaches such as mass spectrometry or protein interaction profiling.
  • An ELISA assay initially comprises preparing an antibody, if not readily available from a commercial source, specific to CSG, preferably a monoclonal antibody.
  • a reporter antibody generally is prepared which binds specifically to CSG.
  • the reporter antibody is attached to a detectable reagent such as radioactive, fluorescent or enzymatic reagent, for example horseradish peroxidase enzyme or alkaline phosphatase.
  • antibody specific to CSG is incubated on a solid support, e.g. a polystyrene dish, that binds the antibody. Any free protein binding sites on the dish are then covered by incubating with a non-specific protein such as bovine serum albumin.
  • a non-specific protein such as bovine serum albumin.
  • the sample to be analyzed is incubated in the dish, during which time CSG binds to the specific antibody attached to the polystyrene dish. Unbound sample is washed out with buffer.
  • a reporter antibody specifically directed to CSG and linked to a detectable reagent such as horseradish peroxidase is placed in the dish resulting in binding of the reporter antibody to any monoclonal antibody bound to CSG. Unattached reporter antibody is then washed out.
  • Reagents for peroxidase activity including a colorimetric substrate are then added to the dish.
  • Immobilized peroxidase, linked to CSG antibodies, produces a colored reaction product.
  • the amount of color developed in a given time period is proportional to the amount of CSG protein present in the sample.
  • Quantitative results typically are obtained by reference to a standard curve.
  • a competition assay can also be employed wherein antibodies specific to CSG are attached to a solid ⁇ support and labeled CSG and a sample derived from the host are passed over the solid support. The amount of label detected which is attached to the solid support can be correlated to a quantity of CSG in the sample.
  • Nucleic acid methods can also be used to detect CSG mRNA as a marker for prostate cancer. Polymerase chain reaction
  • PCR ligase chain reaction
  • LCR ligase chain reaction
  • NASABA reverse- transcriptase PCR
  • RT-PCR reverse- transcriptase PCR
  • RT-PCR an mRNA species is first reverse transcribed to complementary DNA (cDNA) with use of the enzyme reverse transcriptase; the cDNA is then amplified as in a standard PCR reaction.
  • cDNA complementary DNA
  • RT-PCR can thus reveal by amplification the presence of a single species of mRNA. Accordingly, if the mRNA is highly specific for the cell that produces it, RT-PCR can be used to identify the presence of a specific type of cell.
  • Hybridization to clones or oligonucleotides arrayed on a solid support can be used to both detect the expression of and quantitate the level of expression of that gene.
  • a cDNA encoding the CSG gene is fixed to a substrate.
  • the substrate may be of any suitable type including but not limited to glass, nitrocellulose, nylon or plastic.
  • At least a portion of the DNA encoding the CSG gene is attached to the substrate and then incubated with the analyte, which may be RNA or a complementary DNA (cDNA) copy of the RNA, isolated from the tissue of interest.
  • Hybridization between the substrate bound DNA and the analyte can be detected and quantitated by several means including but not limited to radioactive labeling or fluorescence labeling of the analyte or a secondary molecule designed tft detect the hybrid. Quantitation of the level of gene expression can be done by comparison of the intensity of the signal from the analyte compared with that determined from known standards. The standards can be obtained by in vi tro transcription of the target gene, quantitating the yield, and then using that material to generate a standard curve.
  • 2D electrophoresis is a technique well known to those in the art. Isolation of individual proteins from a sample such as serum is accomplished using sequential separation of proteins by different characteristics usually on polyacrylamide gels. First, proteins are separated by size using an electric current. The current acts uniformly on all proteins, so smaller proteins move farther on the gel than larger proteins. The second dimension applies a current perpendicular to the first and separates proteins not on the basis of size but on the specific electric charge carried by each protein. Since no two proteins with different sequences are identical on the basis of both size and charge, the result of a 2D separation is a square gel in which each protein occupies a unique spot. Analysis of the spots with chemical or antibody probes, or subsequent protein microsequencing can reveal the relative abundance of a given protein and the identity of the proteins in the sample.
  • Tissue extracts are obtained routinely from tissue biopsy and autopsy material.
  • Bodily fluids useful in the present invention include blood, urine, saliva or any other bodily secretion or derivative thereof.
  • blood it is meant to include whole blood, plasma, serum or any derivative of blood.
  • CSGs are also useful in the rational design of new therapeutics for imaging and treating cancers, and in particular prostate cancer.
  • antibodies which specifically bind to CSG can be raised and used in vivo in patients suspected of suffering from prostate cancer.
  • Antibodies which specifically bind a CSG can be injected into a patient suspected of having prostate cancer for diagnostic and/or therapeutic purposes.
  • the preparation and use of antibodies for in vivo diagnosis is well known in the art.
  • antibody-chelators labeled with Indium-Ill have been described for use in the radioimmunoscintographic imaging of carcinoembryonic antigen expressing tumors (Sumerdon et al. Nucl . Med. Biol. 1990 17:247-254) .
  • these antibody-chelators have been used in detecting tumors in patients suspected of having recurrent colorectal cancer (Griffin et al . J. Clin. One. 1991 9:631-640) .
  • Antibodies with paramagnetic ions as labels for use in magnetic resonance imaging have also been described (Lauffer, R.B. Magnetic Resonance in Medicine 1991 22:339- 342) .
  • Antibodies directed against CSG can be used in a similar manner. Labeled antibodies which specifically bind CSG can be injected into patients suspected of having prostate cancer for the purpose of diagnosing or staging of the disease status of the patient. The label used will be selected in accordance with the imaging modality to be used.
  • radioactive labels such as Indium-Ill, Technetium-99m or Iodine-131 can be used for planar scans or single photon emission computed tomography (SPECT) .
  • Positron emitting labels such as Fluorine-19 can be used in positron emission tomography.
  • Paramagnetic ions such as Gadlinium (III) or
  • Manganese (II) can be used in magnetic resonance imaging
  • MRI Magnetic resonance Imaging
  • an antibody which specifically binds CSG can also have a therapeutic benefit.
  • the antibody may exert its therapeutic effect alone.
  • the antibody can be conjugated to a cytotoxic agent such as a drug, toxin or radionuclide to enhance its therapeutic effect.
  • Drug monoclonal antibodies have been described in the art for example by Garnett and Baldwin, Cancer Research 1986 46:2407-2412. The use of toxins conjugated to monoclonal antibodies for the therapy of various cancers has also been described by Pastan et al . Cell 1986 47:641-648.
  • Yttrium-90 labeled monoclonal antibodies have been described for maximization of dose delivered to the tumor while limiting toxicity to normal tissues (Goodwin and Meares Cancer Supplement 1997 80:2675-2680).
  • Other cytotoxic radionuclides including, but not limited to Copper-67, Iodine- 131 and Rhenium-186 can also be used for labeling of antibodies against CSG.
  • Antibodies which can be used in these in vivo methods include polyclonal, monoclonal and omniclonal antibodies and antibodies prepared via molecular biology techniques. Antibody fragments and aptamers and single-stranded oligonucleotides such as those derived from an in vi tro evolution protocol referred to as SELEX and well known to those skilled in the art can also be used.
  • Small molecules predicted via computer imaging to specifically bind to regions of CSGs can also be designed and synthesized and tested for use in the imaging and treatment of prostate cancer. Further, libraries of molecules can be screened for potential anticancer agents by assessing the ability of the molecule to bind to CSGs identified herein. Molecules identified in the library as being capable of binding to CSG are key candidates for further evaluation for use in the treatment of prostate cancer.
  • CSGs were carried out by a systematic analysis of data in the LIFESEQ database available from Incyte Pharmaceuticals, Palo Alto, CA, using the data mining Cancer Leads Automatic Search Package (CLASP) developed by diaDexus LLC, Santa Clara, CA.
  • CLASP Cancer Leads Automatic Search Package
  • the CLASP performs the following steps: selection of highly expressed organ specific genes based on the abundance level of the corresponding EST in the targeted organ versus all the other organs; analysis of the expression level of each highly expressed organ specific genes in normal, tumor tissue, disease tissue and tissue libraries associated with tumor or disease; selection of the candidates demonstrating component ESTs were exclusively or more frequently found in tumor libraries.
  • the CLASP allows the identification of highly expressed organ and cancer specific genes.
  • a final manual in depth evaluation is then performed to finalize the CSGs selection .
  • Clones depicted in the following Table 1 are CSGs useful in diagnosing, monitoring, staging, imaging arsd treating prostate cancer. Table 1: CSGs
  • Example 2 Relative Quantitation of Gene Expression Real-Time quantitative PCR with fluorescent Taqman probes is a quantitation detection system utilizing the 5'- 3' nuclease activity of Taq DNA polymerase.
  • the method uses an internal fluorescent oligonucleotide probe (Taqman) labeled with a 5' reporter dye and a downstream, 3' quencher dye.
  • Taqman internal fluorescent oligonucleotide probe
  • the 5' -3' nuclease activity of Taq DNA polymerase releases the reporter, whose fluorescence can then be detected by the laser detector of the Model 7700 Sequence Detection System (PE Applied Biosystems, Foster City, CA, USA) .
  • Amplification of an endogenous control is used to standardize the amount of sample RNA added to the reaction and normalize for Reverse Transcriptase (RT) efficiency.
  • Either cyclophilin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) , ATPase, or 18S ribosomal RNA (rRNA) is used as this endogenous control.
  • GPDH glyceraldehyde-3-phosphate dehydrogenase
  • rRNA 18S ribosomal RNA
  • Quantitation relative to the "calibrator" can be obtained using the standard curve method or the comparative method
  • the tissue distribution and the level of the target gene were evaluated for every sample in normal and cancer tissues.
  • Table 2 The absolute numbers depicted in Table 2 are relative levels of expression of the CSG referred to as Prol09 in 12 normal different tissues . All the values are compared to normal stomach (calibrator) . These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals. Table 2: Relative Levels of CSG Prol09 Expression in Pooled Samples *
  • Table 3 The absolute numbers depicted in Table 3 are relative levels of expression of Prol09 in 28 pairs of matching samples and 4 unmatched samples. All the values are compared to normal stomach (calibrator) . A matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual. Table 3: Relative Levels of CSG Prol09 Expression in Individual Samples *
  • the level of mRNA expression was compared in cancer samples and the isogenic normal adjacent tissue from the same individual. This comparison provides an indication of specificity for the cancer (e.g. higher levels of mRNA expression in the cancer sample compared to the normal adjacent) .
  • Table 3 shows overexpression of Prol09 in 6 out of 9 primary prostate cancer tissues compared with their respective normal adjacents. Thus, overexpression in the can.cer tissue was observed in 66.66% of the prostate matching samples tested (total of 9 prostate matching samples) .
  • RNA samples depicted in Table 4 are relative levels of expression of the CSG Proll2 in 12 normal different tissues. All the values are compared to normal thymus (calibrator). These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals.
  • RNA samples depicted in Table 5 are relative levels of expression of the CSG Prolll in 12 normal different tissues. All the values are compared to normal testis (calibrator) . These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals.
  • the relative levels of expression in Table 5 show that Prolll mRNA expression is extraordinarily high in the pool of normal prostate (1483.72) compared to all the other tissues analyzed with the exception of muscle (5166.6) . These results demonstrate that Prolll mRNA expression shows specificity for prostate and muscle.
  • the absolute numbers in Table 5 were obtained analyzing pools of samples of a particular tissue from different individuals. They cannot be compared to the absolute numbers originated from RNA obtained from tissue samples 'S ' f a single individual in Table 6.
  • the absolute numbers depicted in Table 6 are relative levels of expression of Prolll in 48 pairs of matching and 18 unmatched samples. All the values are compared to normal testis (calibrator) .
  • a matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual.
  • the level of mRNA expression in cancer samples and the isogenic normal adjacent tissue from the same individual were compared. This comparison provides an indication of specificity for cancer (e.g. higher levels of mRNA expression in the cancer sample compared to the normal adjacent) .
  • Table 6 shows overexpression of Prolll in 5 out of 16 primary prostate cancer samples compared with their respective normal adjacent (prostate samples 2, 5,* ' 10, 17, and 19) . Similar expression levels were observed in 3 unmatched prostate cancers (prostate samples 13, 14, 15), 2 prostatitis (prostate samples 20, 21), and 6 benign prostatic hyperplasia samples (prostate samples 22 through 27). Thus, there is overexpression in the cancer tissue of 31.25% of the prostate matching samples tested (total of 16 prostate matching samples ) .
  • RNA samples depicted in Table 7 are relative levels of expression of the CSG Proll5 in 12 normal different tissues. All the values are compared to normal thymus (calibrator) . These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals.
  • the relative levels of expression in Table 7 show that Proll5 mRNA expression is higher (337.79) in prostate compared with all the other normal tissues analyzed. Lung, with a relative expression level of 112.99, and mammary (29.446) are the other tissues expressing moderate levels of mRNA for Proll5. These results establish Proll5 mRNA expression to be highly specific for prostate.
  • the absolute numbers in Table 7 were obtained analyzing pools of samples of a particular tissue from different individuals. They cannot be compared to the absolute numbers originated from RNA obtained from tissue samples of a single individual in Table 8.
  • the absolute numbers depicted in Table 8 are relative levels of expression of Proll5 in 17 pairs of matching and 21 unmatched samples. All the values are compared to normal thymus (calibrator) . A matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual .
  • the levels of mRNA expression in cancer samples and the isogenic normal adjacent tissue from the same individual were compared. This comparison provides an indication of specificity for the cancer (e.g. higher levels of mRNA expression in the cancer sample compared to the normal adjacent) .
  • Table 8 shows higher expression of Proll5 in 3 out of 4 matched prostate cancer tissues (prostate samples 1, 5 & 8) . Altogether, the high level of tissue specificity, plus the. higher expression in 75% of the prostate matching samples tested, are indicative of Proll5 being a diagnostic marker for prostate cancer.
  • RNA samples depicted in Table 9 are relative levels of expression of the CSG ProllO in 12 normal different tissues. All the values are compared to normal small intestine (calibrator) . These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals.
  • the absolute numbers depicted in Table 10 are relative levels of expression of ProllO in 33 pairs of matching samples. All the values are compared to normal small intestine (calibrator) . A matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual . *
  • the levels of mRNA expression in cancer samples and the isogenic normal adjacent tissue from the same individual were compared. This comparison provides an indication of specificity for the cancer (e.g. higher levels of mRNA expression in the cancer sample compared to the normal adjacent) .
  • Table 10 shows overexpression of ProllO in 8 of the 9 primary prostate cancer tissues compared with their respective normal adjacent (except prostate 4) . Thus, there was overexpression in 88.88% of the cancer prostate tissue as compared to the prostate matching samples tested (total of 9 prostate matching samples) .
  • ProllO mRNA expression is upregulated in prostate cancer tissues .
  • the mRNA overexpression in 88.88% of the primary prostate matching cancer samples tested is indicative of ProllO being a diagnostic marker for prostate cancer.
  • ProllO also showed overexpression in several other cancers tested including small intestine, colon, liver, mammary and lung (see Table 10) . Accordingly ProllO may be a diagnostic marker for other types of cancer as well.
  • Expression of Clone ID 1857415; Gene ID 346880 (Proll3)
  • Table 11 The absolute numbers depicted in Table 11 are relative levels of expression of the CSG Proll3 in 12 normal different tissues. All the values are compared to normal thymus (calibrator). These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals.
  • the relative levels of expression in Table 11 show that Proll3 mRNA expression is higher (489.44) in prostate compared with all the other normal tissues analyzed. Testis, with a relative expression level of 0.35, uterus (0.13), thymus (1.0), kidney (0.01) and brain (0.03) were among the other tissues expressing lower mRNA levels for Proll3. These results establish that Proll3 mRNA expression is highly specific for prostate.
  • the absolute numbers in Table 11 were obtained analyzing pools of samples of a particular tissue fro* different individuals . They cannot be compared to the absolute numbers originated from RNA obtained from tissue samples of a single individual in Table 12.
  • the absolute numbers depicted in Table 12 are relative levels of expression of Proll3 in 78 pairs of matching and 25 unmatched tissue samples. All the values are compared to normal thymus (calibrator) .
  • a matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual. In cancers (for example, ovary) where it was not possible to obtain normal adjacent samples from the same individual, samples from a different normal individual were analyzed.
  • prostate cancer samples In the analysis of matching samples, the higher levels of expression were in prostate, showing a high degree of tissue specificity for prostate tissue. In addition to the higher expression levels in prostate cancer samples, Proll3 expression was found to be either induced (where not expressed in normal adjacent tissues) or somewhat upregulated in several other cancers. However, the relative expression and the fold increase in prostate cancer samples far exceeds that in other cancer tissues and is highly significant.
  • the levels of mRNA expression in cancer samples and the isogenic normal adjacent tissue from the same individual were compared. This comparison provides an indication of specificity for the cancer (e.g. higher levels of mRNA expression in the cancer sample compared to the normal adjacent) .
  • Table 12 shows overexpression of Proll3 in 13 out of 16 primary prostate cancer tissues compared with their respective normal adjacent (prostate samples 2, 3, 4, 5, 6 7, 8, 9, 10, 11, 13, 14, 16). Thus, there was overexpression in the cancer tissue for 81.25% of the prostate matching samples tested.
  • the median for the level of expression in prostate cancer tissue samples is 609, whereas the median for all other cancers is only 7.93, with the exception of one colon sample, colon 9, whose expression was similar to that found in prostate cancer tissues.
  • Proll3 being a diagnostic marker for prostate cancer.
  • Expression was also found to be higher in other cancer tissues compared* , with their respective normal adjacent tissues (kidney, bladder, testis, skin, stomach, small intestine, colon, pancreas, lung, mammary, endometrium, uterus, and ovary) thus indicating Proll3 to be a pan cancer marker.
  • RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals. Table 13: Relative Levels of CSG Proll4 Expression in
  • the high level of tissue specificity is indicative of Proll4 being a diagnostic marker for diseases of the prostate, especially cancer.
  • Table 14 The absolute numbers depicted in Table 14 are relative levels of expression of the CSG Proll ⁇ in 12 normal different tissues. All the values are compared to normal kidney (calibrator) . These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals.
  • the absolute numbers in Table 14 were obtained analyzing pools of samples of a particular tissue from different individuals. They cannot be compared to the absolute numbers originated from RNA obtained from tissue samples of a single individual in Table 15.
  • the absolute numbers depicted in Table 15 are relative levels of expression of Proll ⁇ in 59 pairs of matching and 21 unmatched samples. All the values are compared to normal kidney (calibrator) .
  • a matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual .

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Abstract

L'invention concerne de nouvelles méthodes permettant de détecter, de diagnostiquer, de surveiller, de classer par stades, de pronostiquer, de visualiser, et de traiter le cancer de la prostate.
EP99955004A 1998-10-19 1999-10-19 Methode permettant de diagnostiquer, de surveiller, de classer par stades, de visualiser et de traiter le cancer de la prostate Withdrawn EP1131095A4 (fr)

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PCT/US1999/024331 WO2000023111A1 (fr) 1998-10-19 1999-10-19 Methode permettant de diagnostiquer, de surveiller, de classer par stades, de visualiser et de traiter le cancer de la prostate

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US9957569B2 (en) 2005-09-12 2018-05-01 The Regents Of The University Of Michigan Recurrent gene fusions in prostate cancer
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US8945556B2 (en) 2010-11-19 2015-02-03 The Regents Of The University Of Michigan RAF gene fusions
CN117233413A (zh) 2019-08-05 2023-12-15 禧尔公司 用于样品制备、数据生成和蛋白质冠分析的系统和方法

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