WO2012139945A1 - Procédé pour prédire la survie chez des patients cancéreux - Google Patents

Procédé pour prédire la survie chez des patients cancéreux Download PDF

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WO2012139945A1
WO2012139945A1 PCT/EP2012/056157 EP2012056157W WO2012139945A1 WO 2012139945 A1 WO2012139945 A1 WO 2012139945A1 EP 2012056157 W EP2012056157 W EP 2012056157W WO 2012139945 A1 WO2012139945 A1 WO 2012139945A1
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allele
therapy
rsl
alleles
cancer
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Anna GONZÁLEZ NEIRA
Ana PATIÑO GARCÍA
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Universidad De Navarra
Fundación Centro Nacional De Investigaciones Oncológicas Carlos Iii
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    • 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
    • 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
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • 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
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the invention belongs to the field of methods for predicting the clinical outcome of a patient suffering from cancer in response to a therapy.
  • the invention also relates to determining polymorphisms in chemotherapeutic transporter and metabolic pathway genes of the drugs used in standard chemotherapeutic treatment of cancer. BACKGROUND OF THE INVENTION
  • Osteosarcoma is the most common primary bone tumor. The incidence of OS occurs largely in children and adolescents, but 30% of OS also occur in patients over 40 years of age. Treatment by surgery of the affected member results in poor prognosis, with less than 20% expected survival rates due to the development of pulmonary metastasis.
  • the combination of surgery with chemotherapy has lead to a significant improvement compared to surgery alone, and standard treatments of OS currently involve tumor surgical resection and systemic pre- and post-operatory chemotherapy. This combination has achieved patient survival rates of 65-70% at 5 years. However, about 30%) of patients relapse or develop metastasis (Chou & Gorlick, 2006, Expert Rev Anticancer Ther 2006;6: 1075-85).
  • Fellenberg et al. investigated the prognostic significance of eight drug-regulated candidate genes. In this work, it was proven that the increased expression of MALAT-1, IMPDH2, FTL and RHOA significantly correlated with poor response to chemotherapy, and the increased expression of FTL, PHB, ATAD2, ACTN1 and RRM2 as well as increased lactate dehydrogenase serum levels was associated with a decreased overall survival.
  • Pakos & loannidis have described that the expression levels of P-glycoprotein (Pgp) can be used as marker for predicting the risk of progression of patients suffering osteosarcoma which have been treated with chemotherapy.
  • the method for predicting the risk of progression based on the determination of the levels of Pgp requires detecting the protein in the tumor tissue.
  • the authors of the present invention have identified that polymorphisms in two ATP- binding cassette (ABC) genes significantly associated with outcome of patients suffering osteosarcoma treated with chemotherapy.
  • the inventors screened 102 cancer patients, specifically osteosarcoma, for the presence of 366 Single Nucleotide Polymorphisms (SNPs) and 2 copy number variants (CNVs) in 24 genes involved in the metabolism or transport of cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide, and studied the association of the genotypes with tumour response, overall survival, and relevant toxicities (hematological and gastrointestinal).
  • SNPs Single Nucleotide Polymorphisms
  • CNVs 2 copy number variants
  • the invention relates to a method for predicting the clinical outcome of a patient suffering from cancer in response to a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof which comprises determining in a sample from said patient the sequence of at least one polymorphic site selected from the group consisting of the rs4148416, the rs4148737, the rsl 128503 and the rsl0276036 wherein
  • the presence of a T in at least one allele of the rs4148416 site, the presence of a G in at least one allele of the rs4148737, the presence of a C in at least one allele of the rsl 128503 or the presence of a T in at least one allele of the rsl0276036 is indicative of a unfavourable clinical outcome or
  • the presence of a C in at least one allele of the rs4148416 site, the presence of an A in at least one allele of the rs4148737, the presence of a T in at least one allele of the rsl 128503 or the presence of a C in at least one allele of the rsl0276036 is indicative of a favourable clinical outcome.
  • the invention in a second aspect, relates to a method for predicting the efficacy of a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof for treating cancer which comprises determining in a sample from said patient the sequence of at least one polymorphic site selected from the group consisting of the rs4148416, the rs4148737, the rsl 128503 and the rsl0276036 wherein
  • the presence of a T in at least one allele of the rs4148416 site, the presence of a G in at least one allele of the rs4148737, the presence of a C in at least one allele of the rsl 128503 or the presence of a T in at least one allele of the rsl0276036 is indicative of a poor efficacy of the therapy or - the presence of a C in at least one allele of the rs4148416 site, the presence of an A in at least one allele of the rs4148737, the presence of a T in at least one allele of the rsl 128503 or the presence of a C in at least one allele of the rsl0276036 is indicative of a good efficacy of the therapy.
  • the invention relates to a method for selecting a patient suffering from cancer for a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof comprising determining in a sample from said patient the sequence of at least one polymorphic site selected from the group consisting of the rs4148416, the rs4148737, the rsl 128503 and the rsl0276036 wherein the patient is selected if it has a C in at least one allele of the rs4148416 site, the an A in at least one allele of the rs4148737, a T in at least one allele of the rsl 128503 or a C in at least one allele of the rsl0276036.
  • the invention relates to a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof for use in the treatment of a patient suffering from cancer, wherein said patient has been selected by a method according to any of claims 5 to 11.
  • the authors of the present invention have found that four polymorphisms in ABC genes can predict the clinical outcome in patients having been treated with a platinum-based compound, an anthracyclin and an antifolate.
  • the inventors screened 102 cancer patients, specifically osteosarcoma, for 366 Single Nucleotide Polymorphisms (SNPs) and 2 copy number variants (CNVs) in 24 genes involved in the metabolism or transport of cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide, and studied the association of the genotypes with tumour response, overall survival, and relevant toxicities (hematological and gastrointestinal) [see example 1].
  • SNPs Single Nucleotide Polymorphisms
  • CNVs 2 copy number variants
  • the invention relates to a method for predicting the clinical outcome of a patient suffering from cancer in response to a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof (hereinafter, first method of the invention) which comprises determining in a sample from said patient the sequence of at least one polymorphic site selected from the group consisting of the rs4148416, the rs4148737, the rsl 128503 and the rsl0276036 wherein
  • the presence of a T in at least one allele of the rs4148416 site, the presence of a G in at least one allele of the rs4148737, the presence of a C in at least one allele of the rsl 128503 or the presence of a T in at least one allele of the rsl0276036 is indicative of an unfavourable clinical of said patient or
  • the presence of a C in at least one allele of the rs4148416 site, the presence of an A in at least one allele of the rs4148737, the presence of a T in at least one allele of the rsl 128503 or the presence of a C in at least one allele of the rsl0276036 is indicative of a favourable clinical outcome of said patient.
  • the invention relates to the use of at least one polymorphism for predicting the clinical outcome of a patient suffering from cancer to a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof, wherein the polymorphism is selected from the group consisting of the rs4148416 polymorphism, the rs4148737 polymorphism, the rsl 128503 polymorphism, the rs 10276036 and a combination of one or more of the above.
  • the polymorphism is selected from the group consisting of the rs4148416 polymorphism, the rs4148737 polymorphism, the rsl 128503 polymorphism, the rs 10276036 and a combination of one or more of the above.
  • the expression "predicting the clinical outcome of a patient” relates to the likelihood that a patient will have a particular clinical outcome, whether positive or negative. As will be understood by those skilled in the art, the prediction, although preferred to be, need not be correct for 100% of the subjects to be diagnosed or evaluated.
  • a statistically significant portion of subjects can be identified as having an increased probability of having a given outcome. Whether a subject is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student's t-test, Mann- Whitney test, etc. Details are found in Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New York 1983.
  • Preferred confidence intervals are at least 50%, at least 60%), at least 70%, at least 80%, at least 90% at least 95%.
  • the p-values are, preferably 0.05, 0.02, 0.01 or lower.
  • Standard criteria can be used herewith to evaluate the clinical outcome of a patient in response to a therapy.
  • Any parameter which is widely accepted for determining the efficacy of treatments can be used for determining the clinical outcome of a patient in response to a treatment and include, without limitation:
  • DFS disease-free survival
  • objective response which, as used in the present invention, describes the proportion of treated subjects in whom a complete or partial response is observed.
  • tumor control which, as used in the present invention, relates to the proportion of treated subjects in whom complete response, partial response, minor response or stable disease > 6 months is observed.
  • ⁇ progression free survival which, as used herein, is defined as the time from start of treatment to the first measurement of cancer growth.
  • Time to progression relates to the time after a disease is treated until the disease starts to get worse.
  • progression has been previously defined.
  • PFS6 progression free survival
  • OS Overall survival
  • ⁇ median survival which, as used herein, relates to the time at which half of the subjects enrolled in the study are still alive.
  • the clinical outcome is measured as 5-year survival rate.
  • the term “patient” is a subject suffering from cancer.
  • subject refers to all animals classified as mammals and includes, but is not restricted to, domestic and farm animals, primates and humans, e.g., human beings, non-human primates, cows, horses, pigs, sheep, goats, dogs, cats or rodents.
  • the subject is a male or female human of any age or race.
  • cancer refers to diseases in which abnormal cells divide without control and can invade nearby tissues, and includes, but is not restricted to, acute lymphoblastic leukemia, acute myelogenous leukemia, bladder cancer, bone sarcoma, breast cancer, cervical cancer, chorioadenoma destruens, choriocarcinoma, gastric cancer, Hodgkin lymphoma, hydatidiform mole, lung cancer, malignant mesothelioma, mycosis fungoides (a type of cutaneous T-cell lymphoma), neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, small cell lung cancer, soft tissue sarcoma, squamous cell carcinoma of the head and neck, testicular cancer, thyroid cancer, transitional cell bladder cancer, Wilms tumor and the like.
  • acute lymphoblastic leukemia acute myelogenous leukemia
  • bladder cancer bone sar
  • the cancer corresponds to those types of tumors which respond to a combination of platinum-based compound, an anthracyclin and an antifolate and, in particular, to the combination known as cisplatin, metrothexate and adriamycin.
  • the cancer corresponds to tumors which respond to a combination of platinum-based compound, a mitotic inhibitor, an anthracyclin and an antifolate and, in particular, to the combination of cisplatin, vincristine, adriamycin and methotrexate (CVAM).
  • the cancer corresponds to tumors which respond to a combination of platinum-based compound, an anthracyclin, an antifolate and an alkylating agent and a mitotic inhibitor, in particular, to the combination of cisplatin, adriamycin, methotrexate, cyclophosphamide and vincristine.
  • the cancer corresponds to those types of tumors which respond to a combination of cisplatin, metrothexate and adriamycin, such as osteosarcoma.
  • the cancer is osteosarcoma.
  • osteosarcoma refers to an aggressive cancerous neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid. Osteosarcoma is classified into low-grade and high-grade according to the appearance of the cancer cells. Low-grade osteosarcoma is characterized by cancer cells with normal appearance, with slow growth and high-grade osteosarcoma is characterized by cancer cells with very abnormal appearance, with rapid growth and more likely to spread. Most osteosarcomas are high-grade, but a type known as a parosteal osteosarcoma is usually low-grade. A further subtype (periosteal osteosarcoma) is usually treated as though it was high-grade. In addition, osteosarcoma can be classified according to its localization in the following stages:
  • Stage 1A low-grade osteosarcoma completely contained within the hard coating of the bone
  • Stage IB low-grade osteosarcoma extending outside the bone into the soft tissue spaces, which contain nerves and blood vessels;
  • Stage 2A high-grade osteosarcoma completely contained within the hard coating of the bone
  • Stage 2B high-grade osteosarcoma extending outside the bone into the soft tissue spaces, which contain nerves and blood vessels. Most osteosarcomas are stage 2B;
  • Stage 3 low-grade or high-grade osteosarcoma found either within the bone or extending outside the bone, that has metastasized.
  • the osteosarcoma is conventional high-grade osteosarcoma, regardless of metastatic stage at diagnosis. Its most frequent subtypes are osteoblastic, chondroblastic and fibroblastic osteosarcomas.
  • the cancer is osteosarcoma and the patient is a child, an adolescent or a young adult.
  • the term "child” as used herein refers to a human person having not more than 12 years of age, and includes children from about 12 months to about 12 years of age.
  • the term "adolescent” is defined as a human person whose age is between about 12 years and about 16 years.
  • the term "young adult” is used herein to identify a human person between about 16 years and 40 years of age.
  • the first method of the invention allows the skilled person to predict the clinical outcome of a patient suffering cancer in response to a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof.
  • the term "therapy”, as used herein, refers to a therapeutic treatment, as well as a prophylactic or prevention method, wherein the goal is to prevent or reduce an unwanted physiological change or disease, such as cancer.
  • Beneficial or desired clinical results include, but not limiting, release of symptoms, reduction of the length of the disease, stabilized pathological state (specifically not deteriorated), retard in the disease's progression, improve of the pathological state and remission (both partial and total), both detectable and not detectable.
  • the therapy can be neoadjuvant chemotherapy, adjuvant chemotherapy or surgery.
  • the terms “treat” and “treatment” are synonyms of the term “therapy” and can be used without distinction along the present description. "Treatment” can mean also prolong survival, compared to the expected survival if the treatment is not applied.
  • the therapy is selected from the group consisting of neoadjuvant chemotherapy, adjuvant chemotherapy and a combination thereof.
  • nanoadjuvant chemotherapy refers to systemic drug treatment given to people with cancer prior to surgery which aim is to reduce the size or extent of the cancer before receiving surgery, thus making procedures easier and more likely to be successful, and reducing the consequences of a more extensive surgery that would have to be done if the tumor was not reduced in size or extent.
  • adjuvant chemotherapy relates to additional treatment, usually given after surgery where all detectable disease has been removed, but where there remains a statistical risk of relapse due to occult disease.
  • chemotherapy plays a significant part in cancer treatment, as it is required for the treatment of advanced cancers with distant metastasis and often helpful for tumor reduction before surgery (neoadjuvant therapy). It is also used following surgery or radiation (adjuvant therapy) to destroy any remaining cancer cells or prevent recurrence of the cancer.
  • the patient has undergone surgical resection of the tumor.
  • alkylating agents that act directly on the DNA (such as cisplatin, carboplatin, oxaliplatin, busulfan, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine); antimetabolites that interfere with DNA and RNA synthesis (such as 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine (ara-C), fludarabine); anthracyclines that interfere with enzymes involved in DNA replication (such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone); microtubule disrupters (taxanes such as paclitaxel and docetaxel or Vinca alkaloids such as vinblastine, vincristine, and vinorelbine); topoisomerase inhibitors (such as etoposide,
  • the therapy used in the first method according to the invention is selected from the group consisting of a platinum-based compound, an anthracyclin, an antifolate or a combination thereof.
  • a platinum-based chemotherapy or a “platinum-based chemotherapeutic treatment” is understood as any treatment which includes at least a platinum-based compound.
  • platinum-based compound refers to any compound containing a platinum atom capable of binding and cross-linking DNA, inducing the activation of the DNA repair and ultimately triggering apoptosis.
  • Platinum-based compounds suitable for treating osteosarcoma include, without limitation, carboplatin, cisplatin [cis-diamminedichloroplatinum, (CDDP)], oxaliplatin, iproplatin, nedaplatin, triplatin tetranitrate, tetraplatin, satraplatin and the like.
  • the platinum-based compound is selected from carboplatin, cisplatin and oxaliplatin.
  • anthracyclines or “anthracyclin antibiotics”, as used herein, refers to a class of drugs used in cancer chemotherapy derived from Streptomyces bacteria. They have three mechanisms of action:
  • the anthracyclin is doxorubicine/adriamycin.
  • antifolates refers to drugs which impair the function of folic acids.
  • Non-limiting examples of antifolates include methotrexate, trimethoprim, pyrimethamine and pemetrexed.
  • Antifolates act specifically during DNA and RNA synthesis, and thus are cytotoxic during the S-phase of the cell cycle, inhibiting the growth and proliferation of non-cancerous cells.
  • the antifolate is methotrexate.
  • the therapy further comprises an alkylating agent, an antimitotic vinca alkaloid and a combination thereof.
  • alkylating agent refers to an agent that attaches an alkyl group (C n H 2n+ i) to DNA and includes, without limitation, including cyclophosphamide, ifosfamide, thiotepa, busulfan, melphalan, chloroethylnitrosourea, Mechlorethamin, Chlorambucil and the like.
  • antimitotic vinca alkaloid refers to compounds that inhibit cell proliferation by binding to microtubules, which leads to a mitotic block and apoptosis.
  • Non-limiting examples of antimitotic vinca alkaloids are vinblastine, vincristine, vindesine and navelbine.
  • the first method of the invention comprises determining in a sample from said patient the sequence of at least one polymorphic site selected from the group consisting of the rs4148416, the rs4148737, the rsl 128503 and the rsl0276036
  • sample relates to any non-tumor sample which can be obtained from the subject.
  • the present method can be applied to any kind of biological non-tumor sample from a subject, such as a biopsy sample, tissue, cell or fluid (serum, saliva, semen, sputum, cerebral spinal fluid (CSF), tears, mucus, sweat, milk, brain extracts and the like).
  • said sample is a biofluid sample, preferably, a peripheral blood sample.
  • said sample may also be a sample from an oral mucosa.
  • Said samples can be obtained by conventional methods, e.g., swab, biopsy, etc. by using methods well known to those of ordinary skill in the related medical arts. Methods for obtaining the sample from the biopsy include gross apportioning of a mass, or microdissection, Tru-Cut biopsy or other art-known cell-separation methods.
  • the first method of the invention comprises determining in a sample from the patient the sequence of at least one polymorphic site selected from the group consisting of the rs4148416, the rs4148737, the rsl 128503 and the rsl0276036.
  • polymorphism relates to a variation in the nucleotide sequence of a nucleic acid wherein each possible sequence is present in a proportion equal to or greater than a 1% of the population.
  • SNP Single Nucleotide Polymorphism
  • polymorphisms are typically named using the accession number in the Single Nucleotide Polymorphism (SNP) database (dbSNP) at National Center for Biotechnology Information (NCBI) accessible at http://www.ncbi.nlm.nih.gov/projects/SNP/.
  • SNP Single Nucleotide Polymorphism
  • NCBI National Center for Biotechnology Information
  • the polymorphism can be named as well by indicating the position at the gene or genomic contig wherein the variation occurs and the type of nucleotide change that occurs at said position or the type of amino acid change in the polypeptide encoding by said gene.
  • the polymorphism is named as follows “aal-nn-aa2", wherein “aal” represents the original amino acid, “nn” corresponds to the position of the mutated amino acid, and “aa2" represents the amino acid resulting from the mutation.
  • nucleotide change does not correspond with any change in the corresponding amino acid
  • polymorphism is named indicating the position of the nucleotide which contains the mutation and the nucleotide change is indicated as follows “mm ntl>nt2", wherein “mm” indicates the number of the nucleotide in which the change has occurred, “ntl” represents the original nucleotide and "nt2" the changed nucleotide.
  • the polymorphisms to be detected are selected from the group consisting of the rs4148416, the rs4148737, the rsl 128503 and the rsl0276036.
  • the polymorphism rs4148416 is located in the ABCC3 gene, and corresponds to the sequence (SEQ ID NO: 1):
  • the rs4148416 polymorphism is also referred to as the G1013G polymorphism.
  • the polymorphism rs4148737 is located in the ABCB1 gene, and corresponds to the sequence (SEQ ID NO: 2):
  • the polymorphism rsl 128503 is located in the ABCB1 gene, and corresponds to the sequence (SEQ ID NO: 3):
  • the polymorphism rs 10276036 is located in the ABCB1 gene, and corresponds to the sequence (SEQ ID NO: 4):
  • allele is used in the present description and relates to a polymorphism occurring in one and the same locus in one and the same population.
  • SNP genotyping is the measurement of single nucleotide polymorphisms (SNPs).
  • SNPs single nucleotide polymorphisms
  • the genotype the result of one SNP in one subject is determined from a sample of the nucleic acid from the subject.
  • the detection of the polymorphism in the method of the invention can be performed by means of multiple processes known by the person skilled in the art. In those cases wherein the determination of the polymorphisms is carried out in a biofluid and, in particular, in whole blood, the whole blood may be utilized directly for identification and quantification of the mutant DNA.
  • nucleic acid is extracted from whole blood as an initial step of the invention. In such cases, the total DNA extracted from said samples would represent the working material suitable for subsequent amplification.
  • Isolating the nucleic acid of the biological sample can be performed by methods known by the person skilled in the art. Said methods can be found, for example, in Sambrook et al, 2001. "Molecular cloning: a Laboratory Manual", 3rd ed., Cold Spring Harbor Laboratory Press, N.Y., Vol. 1-3.
  • Systems and methods for the detection of polymorphisms associated to genes include, but are not limited to, hybridization methods and array technology (e.g. technology available from Aclara Biosciences, Affymetrix, Agilent Technologies, Inc., etc), techniques based on mobility shift in amplified nucleic acid fragments, Single Stranded Conformational Polymorphism (SSCP), denaturing grandient gel electrophoresis (DGGE), Chemical mismatch cleavage (CMC), Restriction fragment polymorphisms (RFLPs), WAVE analysis can be used (Methods Mol. Med. 2004; 108: 173-88), nucleic acid sequencing and the like.
  • array technology e.g. technology available from Aclara Biosciences, Affymetrix, Agilent Technologies, Inc., etc
  • techniques based on mobility shift in amplified nucleic acid fragments Single Stranded Conformational Polymorphism (SSCP), denaturing grandient gel electrophoresis (DGGE), Chemical mismatch cleavage
  • nucleic acids for analysis from samples generally requires nucleic acid amplification.
  • Many amplification methods rely on an enzymatic chain reaction (such as a polymerase chain reaction, a ligase chain reaction, or a self-sustained sequence replication, rolling-circle amplification assays, invasive excision assays, use of mass spectroscopy, hybridization assays using a probe complementary to the polymorphism, primer extension assay, enzyme cleavage methods, NASBA, sandwich hybridization methods, methods using molecular markers, ligase chain reactions and the like.
  • Methods for carrying out the detection of polymorphisms are described in Sambrook et al, 2001 (cited at supra) and in patent application US2007/0105128.
  • Real-time PCR also known as Quantitative PCR, Real-time Quantitative PCR, or RTQ- PCR
  • Quantitative PCR is a method of simultaneous DNA quantification and amplification (Expert Rev. Mol. Diagn. 2005(2):209-19).
  • DNA is specifically amplified by polymerase chain reaction. After each round of amplification, the DNA is quantified.
  • Common methods of quantification include the use of fluorescent dyes that intercalate with double-strand DNA and modified DNA oligonucleotides (called probes) that fluoresce when hybridised with a complementary DNA.
  • amplification can be carried out using primers that are appropriately labelled, and the amplified primer extension products can be detected using procedures and equipment for detection of the label.
  • probes of this invention are labeled with at least one detectable moiety, wherein the detectable moiety or moieties are selected from the group consisting of: a conjugate, a branched detection system, a chromophore, a fluorophore, a spin label, a radioisotope, an enzyme, a hapten, an acridinium ester and a luminescent compound.
  • the primers used can labelled with a fluorophore.
  • the reverse primer of the method of the present invention is labelled with the 6-FAM fluorophore at its 5' end.
  • This fluorophore emits fluorescence with a peak wavelength of 522 nm.
  • the PCR can be carried out using one of the primers labelled with, for example, either FAM, HEX, VIC or NED dyes.
  • the first method of the invention further comprises determining whether the clinical outcome of a patient in response to a therapy based on platinum-based compound, an anthracyclin and/or an antifolate will be favourable or unfavourable. This determination is carried out as follows:
  • unfavourable clinical outcome refers to not obtaining beneficial or desired clinical results which can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • favourable clinical outcome refers to obtaining beneficial or desired clinical results which can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • the clinical outcome is considered as favourable if the overall survival at five years of the patient is higher than that of patients not carrying the polymorphisms.
  • the prediction according to the first method of the invention is carried out as follows:
  • homozygous is defined as a genetic condition existing when identical alleles reside at corresponding loci on homologous chromosomes.
  • the invention relates to a method for predicting the efficacy of a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof for treating cancer (hereinafter, second method of the invention) which comprises determining in a sample from said patient the sequence of at least one polymorphic site selected from the group consisting of the rs4148416, the rs4148737, the rsl 128503 and the rsl0276036 wherein
  • the presence of a T in at least one allele of the rs4148416 site, the presence of a G in at least one allele of the rs4148737, the presence of a C in at least one allele of the rsl 128503 or the presence of a T in at least one allele of the rsl0276036 is indicative of a poor efficacy of the therapy or
  • the presence of a C in at least one allele of the rs4148416 site, the presence of an A in at least one allele of the rs4148737, the presence of a T in at least one allele of the rsl 128503 or the presence of a C in at least one allele of the rsl0276036 is indicative of a good efficacy of the therapy.
  • predicting the efficacy of a therapy refers to determine the clinical outcome of a patient suffering cancer in response to a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof.
  • the invention in another aspect, relates to a method for selecting a patient suffering from cancer for a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof (hereinafter, third method of the invention) comprising determining in a sample from said patient the sequence of at least one polymorphic site selected from the group consisting of the rs4148416, the rs4148737, the rsl 128503 and the rsl0276036 wherein the patient is selected if it has a C in at least one allele of the rs4148416 site, an A in at least one allele of the rs4148737, a T in at least one allele of the rsl 128503 or a C in at least one allele of the rsl0276036.
  • the patient is selected if it has C in both alleles of the rs4148416 site, A in both alleles of the rs4148737, T in both alleles of the rsl 128503 or C in both alleles of the rsl0276036. All the particular embodiments disclosed previously for the first method of the invention are also applicable to the second and third methods of the invention, such as
  • the cancer is osteosarcoma
  • the platinum-based compound is cisplatin, the anthracyclin is adriamycin, and/or the antifolate is methotrexate;
  • the sample from a patient is a biofluid sample, preferably, blood;
  • the determination of the sequence at one or more of the polymorphic sites comprises the use of at least one oligonucleotide specific for one of the alleles of said polymorphic site or sites; etc.
  • the definitions and techniques provided for the first method of the invention are also applicable to the second and third methods of the invention. Use of reagents suitable for detection of the sequence of a polymorphic site selected from the group consisting of the rs4148416. the rs4148737.
  • the invention relates to the use of a reagent suitable for the detection of the sequence of a polymorphic site selected from the group consisting of the rs4148416, the rs4148737, the rsl 128503 and the rsl0276036 sites for predicting the clinical outcome of a patient in response to a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof for predicting the efficacy of a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof, or for selecting a patient suffering from cancer for a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof.
  • the cancer is osteosarcoma.
  • the reagent suitable for the detection of a polymorphic site may be a probe which is able to distinguish a particular form of the gene or the presence or a particular variance or variances, e.g., by differential binding or hybridization.
  • exemplary probes include nucleic acid hybridization probes, peptide nucleic acid probes, nucleotide- containing probes which also contain at least one nucleotide analogue, and antibodies, e.g., monoclonal antibodies, and other probes as discussed herein. Those skilled in the art are familiar with the preparation of probes with particular specificities.
  • nucleic acid hybridization probe may span two or more variance sites.
  • a nucleic acid probe can include one or more nucleic acid analogs, labels or other substituents or moieties so long as the base-pairing function is retained.
  • the invention relates to a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof for use in the treatment of a patient suffering from cancer, wherein said patient has been selected by the third method of the invention.
  • the invention relates to the use of a therapeutic composition or combination comprising a platinum-based compound, an anthracyclin, an antifolate or a combination thereof for the manufacture of a medicament for the treatment of cancer wherein the composition is to be administered to a patient suffering from cancer, wherein said patient has been selected by the third method of the invention.
  • the invention in another aspect, relates to a method for the treatment of cancer in a subject in need therof which comprises the administration to said patient of a therapy based on a platinum-based compound, an anthracyclin, an antifolate or a combination thereof for use in the treatment of a patient suffering from cancer, wherein the patient has been selected by the third method of the invention.
  • treating or its grammatical equivalents as used herein, means achieving a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • the platinum-based compound, an anthracyclin, an antifolate or a combination thereof can be administered to patients as known in the art.
  • the route of administration may oral, intravenous (i.v.), intraarterial (i.a.), intramuscular (i.m.), subcutaneous (s.c), intradermal (i.d.), intraperitoneal (i.p.), intrathecal (i.t.), intrapleural, intrauterine, rectal, vaginal, topical, intratumor and the like.
  • the platinum-based compound, an anthracyclin, an antifolate or a combination thereof can be administered parenterally by injection or by gradual infusion over time and can be delivered by peristaltic means.
  • the cancer is osteosarcoma and the platinum-based compound is administered intraarterially in neo-adjuvant therapy, and intravenously in adjuvant therapy.
  • the platinum-based compound, an anthracyclin, an antifolate or a combination thereof are administered orally by administration of a unit dose.
  • unit dose when used in reference to a therapeutic composition of the present invention refers to physically discrete units suitable as unitary dosage for the subject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent; i.e., carrier, or vehicle.
  • compositions are administered in a manner compatible with the dosage formulation, and in a therapeutically effective amount.
  • quantity to be administered and timing depends on the subject to be treated, capacity of the subject's system to utilize the active ingredient, and degree of therapeutic effect desired. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each individual.
  • platinum-based compound an anthracyclin, an antifolate or a combination thereof useful for practicing the methods of the present invention are described herein.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof.
  • the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the active ingredient.
  • the platinum-based compound, an anthracyclin, an antifolate or a combination thereof to be administered according to the present invention can include pharmaceutically acceptable salts of the components therein.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide) that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, tartaric, mandelic and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethyl amino ethanol, histidine, procaine and the like. Physiologically tolerable carriers are well known in the art.
  • liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate-buffered saline. Still further, aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, polyethylene glycol and other solutes. Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerin, vegetable oils such as cottonseed oil, and water-oil emulsions.
  • platinum-based compound is cisplatin
  • the anthracyclin is adriamycin and/or the antifolate is methotrexate.
  • the composition further comprises an alkylating agent, an antimitotic vinca alkaloid or a combination thereof.
  • the alkylating agent is cyclophosphamide and/or the antimitotic vinca alkaloid is vincristine.
  • cancer has been described in detail above. In a particular embodiment, the cancer is osteosarcoma.
  • Kits of the invention The present invention also contemplates the preparation of kits for use in accordance with the present invention.
  • Suitable kits include various reagents for use in accordance with the present invention in suitable containers and packaging materials, including tubes, vials, and shrink-wrapped and blow-molded packages.
  • Materials suitable for inclusion in an exemplary kit in accordance with the present invention comprise one or more of the following: gene specific PCR primer pairs (oligonucleotides) that anneal to DNA or cDNA sequence domains that flank the genetic polymorphisms of interest, reagents capable of amplifying a specific sequence domain in either genomic DNA or cDNA without the requirement of performing PCR; reagents required to discriminate between the various possible alleles in the sequence domains amplified by PCR or non-PCR amplification (e.g., restriction endonucleases, oligonucleotide that anneal preferentially to one allele of the polymorphism, including those modified to contain enzymes or fluorescent chemical groups that amplify the signal from the oligonucleotide and make discrimination of alleles more robust); reagents required to physically separate products derived from the various alleles (e.g.
  • kits comprising two or more polymorphism-specific or allele- specific oligonucleotides or oligonucleotide pairs, wherein each polymorphism-specific or allele-specific oligonucleotide or oligonucleotide pair is directed to one of the polymorphisms recited herein.
  • the present invention contemplates a kit comprising one or more polymorphism-specific or allele-specific oligonucleotide or oligonucleotide pair directed to one or more of the polymorphisms selected from the group consisting of the rs4148416 polymorphism, the rs4148737 polymorphism, the rsl 128503 polymorphism, the rsl 0276036 and a combination of one or more of the above.
  • directed to means an oligonucleotide or oligonucleotide pair capable of identifying the allele present at the polymorphism.
  • the kit comprises one or more polymorphism-specific or allele- specific oligonucleotides or oligonucleotide pairs directed to two or more of the above polymorphisms, while in another embodiment the kit comprises one or more polymorphism- specific or allele-specific oligonucleotides or oligonucleotide pairs directed to all three of the above polymorphisms.
  • adriamycin 3 courses at 25- 30 mg/m2/day for 3 days
  • i.v. methotrexate 4 courses of up to 14 g/m2/day for 1 day
  • intra-arterial cisplatin 3 courses at 35 mg/m2/day for 3 days
  • the adjuvant chemotherapy included methotrexate (10 g/m2/day for 1 day and folinic acid rescue) and alternate cycles of i.v. cisplatin/adriamycin or i.v. actinomycin D (0.45 mg/m2/day for 3 days), cyclophosphamide (500 mg/m2/day for 3 days), and vincristine (1.5 mg/m2/day for 1 day) for up to 48 weeks of treatment.
  • Peripheral blood samples were collected from patients in remission or at the time of initial diagnosis, with their informed consent, and data were encrypted, anonymized, and linked to their clinical data.
  • Genomic DNA was extracted from peripheral blood lymphocytes using standard phenol-chloroform extraction protocols. DNA was quantified using PicoGreen (Invitrogen Corp., Carlsbad, CA).
  • Candidate genes and selection of polymorphisms A total of 24 candidate genes reported to be involved in the metabolism or influx/efflux of the 5 drugs (cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide) were selected, based on the information available in the Pharmacogenomics Knowledge database PharmaGKB (www.pharmgkb .com). These genes encode the following proteins:
  • MPO Phase I metabolism enzymes: SOD1, ALDH1A1, CYP3A4, 3A5, 2A6, 2B6, 2C8, 2C19, 2C9;
  • both S Ps with potentially functional effects (causing amino acid changes, potentially causing alternative splicing, in the promoter region, in putative transcription factor binding sites, or disrupting miRNAs and their targets) identified using the bioinformatics tool PupaSuite (http://bioinfo.cipf.es/pupasuite/www/index.j sp), and other functional SNPs already described in the literature were selected.
  • This preliminary list of SNPs was filtered using as criteria suitability for the Illumina genotyping platform (selecting only those with an assay score >0.6, associated with a high success rate) and minor allele frequencies (MAFs) of at least 5%.
  • CEPH trios (Coriell Cell Repository, Camden, NJ) were genotyped across the plates. SNPs showing Mendelian allele-transmission errors or showing discordant genotypes were excluded from the analysis.
  • GSTM1 and GSTT1 copy number assays GSTT1 and GS M1 copy number was calculated using Taqman Copy Number Assays (Hs00010004_cn probe for GSTT1 and Hs02575461_cn for GSTMl, Applied Biosystems, Foster City, CA) following the manufacturer's protocol on an ABI PRISM 7900 Sequence Detection System (Applied Biosystems). RNAse P was used as the reference in TaqMan Copy Number Reference Assays. Data were analyzed using absolute quantification of resulting Ct values generated on the sequence detection system. Copy number was estimated using the CopyCaller 1 .0 software (Applied Biosystems). Each sample was evaluated in triplicate.
  • tumour response was assessed using logistic regression analysis, comparing genotype frequencies in good responders and poor responders and estimating odds ratios (OR). Homozygotes for the most frequent allele were used as the reference group. SNPs were then assessed in relation to overall survival using Cox regression analysis. Tumour location (femur, tibia, arm, and central), and metastasis at diagnosis were included as covariates in multivariable logistic regression and Cox regression analyses.
  • the PLIMC and R (version 2.6.0.2) software were used for all analyses, while the SPSS software (version 15.0, SPSS Inc., Chicago, IL, USA) was used for generating Kaplan- Meier curves.
  • the main clinical data for the 102 osteosarcoma patients are presented in Table 1.
  • the median age at diagnosis was 14 years (range 3 to 34 years).
  • the median follow-up was 231 months (range 3-303).
  • genotype data for GSTMl were available for 98 patients, whereas data were available for 99 patients for the GSTTl CNV.
  • the frequency of the homozygous gene deletion for GSTMl was 52% (51 patients) and only 19% (19 patients) for GSTT1.

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Abstract

La présente invention concerne des procédés pour prédire le résultat clinique de patients cancéreux, et en particulier de patients atteints d'ostéosarcome, en réponse à une chimiothérapie basée sur un composé à base de platine, une anthracycline, un antifolate, lesdits procédés étant basés sur la présence de polymorphismes particuliers dans des gènes codant pour des transporteurs ABC. L'invention concerne en outre des procédés pour prédire l'efficacité d'une thérapie basée sur un composé à base de platine, une anthracycline et un antifolate ainsi que des procédés pour un médicament personnalisé chez des patients comportant lesdits polymorphismes.
PCT/EP2012/056157 2011-04-14 2012-04-04 Procédé pour prédire la survie chez des patients cancéreux WO2012139945A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109609642A (zh) * 2019-01-18 2019-04-12 浙江大学 一种检测上皮性卵巢癌易感性的试剂盒
CN109609642B (zh) * 2019-01-18 2021-12-14 浙江大学 一种检测上皮性卵巢癌易感性的试剂盒
CN111500729A (zh) * 2020-05-14 2020-08-07 中国人民解放军总医院 血浆lnc-SCA7在制备判断患者是否对新辅助化疗敏感的生物标志物中的应用
CN111500729B (zh) * 2020-05-14 2022-02-01 中国人民解放军总医院 血浆lnc-SCA7在制备判断患者是否对新辅助化疗敏感的生物标志物中的应用

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