WO2009015799A2 - Détection de la résistance au platine - Google Patents

Détection de la résistance au platine Download PDF

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Publication number
WO2009015799A2
WO2009015799A2 PCT/EP2008/005965 EP2008005965W WO2009015799A2 WO 2009015799 A2 WO2009015799 A2 WO 2009015799A2 EP 2008005965 W EP2008005965 W EP 2008005965W WO 2009015799 A2 WO2009015799 A2 WO 2009015799A2
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WO
WIPO (PCT)
Prior art keywords
platinum
patients
genes
sensitive
gene expression
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PCT/EP2008/005965
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German (de)
English (en)
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WO2009015799A3 (fr
Inventor
Michael Bonin
Jessica Hoffmann
Michael Walter
Olaf Riess
Hans Neubauer
Tanja Fehm
Erich Solomayer
Diethelm Wallwiener
Karl Sotlar
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Eberhard-Karls-Universität Tübingen
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Publication of WO2009015799A2 publication Critical patent/WO2009015799A2/fr
Publication of WO2009015799A3 publication Critical patent/WO2009015799A3/fr

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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
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • 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
    • C12Q2600/142—Toxicological screening, e.g. expression profiles which identify toxicity
    • 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
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to a method of classifying a patient as platinum-sensitive or platinum-resistant, to using the expression profile of a subset of genes to classify a patient as platinum-sensitive or platinum-resistant, and to a method of identifying informative genes to classify a patient as platinum-sensitive or platinum-resistant ,
  • cytostatic agents that act in different ways toxic to the body's own cells and so inhibit cell growth and division.
  • Important cytostatics are based on the ingredient platinum, such as the Cisplatin ® , Eloxatin ® (Oxaliplatin) or Carboplat ® (Carboplatin).
  • platinum-based cytostatic agents are ovarian carcinoma, testicular, bronchial, bladder and cervical carcinomas and squamous cell carcinomas of the head and neck. Platinum-based cytostatic drugs are usually given as an infusion and often used in combination with other chemotherapeutic agents.
  • Ovarian cancer or ovarian cancer, is one of the most common malignancies in women. The incidence is currently 23 per one hundred thousand. In 2000, approximately 9,671 women were diagnosed with ovarian cancer in Germany for the first time; Source: Robert Koch Institute Berlin. In the USA, about 20,000 new cases were expected in 2006, ie about 3% of all tumors in women, and about 15,300 deaths; Source: American Cancer Society: Cancer Facts and Figures 2006, Atlanta, GA: American Cancer Society 2006.
  • the tumor's response to purine chemotherapy was classified using a method that determined the so-called clinical response. Depending on the size of the tumor foci following therapy, as determined by imaging techniques such as ultrasound, the response rates will become complete response, partial response, stable disease, and disease progression ("progression") divided.
  • Platinum-sensitive means according to the invention in accordance with the guidelines of the German Society of Gynecology and Obstetrics, that a tumor patient or a tumor patient with such a platinum-containing substance, for example.
  • a cytostatic agent such as cisplatin or carboplatin, is treatable that it within six months no relapse (recurrence) occurs after completion of therapy.
  • platinum-resistant means according to the invention that a patient with a platinum-containing substance is not appropriately treatable and that a recurrence occurs within six months after completion of the chemotherapy.
  • a biological sample of a patient according to the invention contains representative genetic material of the patient to be classified biological tissue, for example in the form of DNA and / or RNA, which allows the determination of a gene expression profile. Therefore, a biological sample comprises a biological cell, a tissue or tissue part, an organ or organ part, whereby the sample can be provided in liquid or solid form, also in cryopreserved form.
  • Typical biological material originates from a tumor, such as an ovarian carcinoma, which can be obtained by a surgical procedure in the patient to be classified.
  • Gene expression profile is understood to mean the entirety of the transcriptional activity of a multiplicity of genes of an individual, for example of the patient to be classified.
  • Gene expression profiles can be determined by techniques known to those skilled in the art, for example with the aid of DNA microarrays which are equipped with a representative number of different cDNA molecules, to which the genetic material of the individual, for example with a Marker provided mRNA molecules or cDNA molecules generated therefrom, can hybridize.
  • the hybridization activity indicates which genes are expressed in the individual. Furthermore, a statement about the strength of the expression is possible.
  • the compilation of the hybridization activities of all investigated molecules or transcripts makes it possible to produce a gene expression profile of the patient.
  • Similarity with a reference gene expression profile according to the invention means that the transcriptional activity of one or more genes from the specified subgroup corresponds more closely to the transcriptional activity of the corresponding gene or genes from one reference group than to the transcriptional activity of the corresponding gene or genes from the other reference group.
  • This similarity according to the invention can be determined by means of mathematical methods known in the art. This takes place, for example, via so-called “support vector machines” (SVM).
  • SVM support vector machines
  • An SVM fits into a mathematical space a multidimensional hyperplane that serves as a separation plane between two different groups or classes.
  • the gene expression profile determined for a patient can be represented by a mathematical vector which occupies a specific position in the mathematical space.
  • the gene expression profile of the patient is either similar to the reference gene expression profile from the platinum-sensitive patients (1st class) or to the reference gene expression profile from the platinum-resistant patients (2nd class).
  • HGNC HUGO Gene Nomenclature Committee
  • NCBI National Center for Biotechnology Information
  • the problem underlying the invention is hereby completely solved.
  • the inventors have each analyzed twelve platinum-sensitive and platinum-resistant ovarian carcinoma samples and were able to detect 102 different genes or transcripts which show a different expression profile in platinum-sensitive patients than in platinum-resistant patients. From these genes, in turn, the inventors were able to identify 55 different genes which are particularly suitable for classifying a patient to be examined, for example a patient suffering from an ovarian carcinoma, as platinum-sensitive or platinum-resistant. This group of genes is also called a "gene predictor set".
  • the inventors have tested the method according to the invention on 18 different cryopreserved tumor samples from patients for whom a classification into platinum-sensitive and platinum-resistant has already been carried out using classical clinical parameters, so that it was already known whether platinum resistance or platinum sensitivity existed. The result was a 100% correct prediction of the platinum resistance of the samples.
  • the method according to the invention is therefore particularly reliable.
  • Another object of the present invention is the use of the gene expression profile of a subset of genes for classifying a patient as platinum-sensitive or platinum-resistant, wherein the subset of genes consists of at least one gene selected from the group of genes described above.
  • This measure has the advantage that the accuracy of the classification of a patient in platinum-sensitive or platinum-resistant is further increased.
  • a highly reliable classification is already made possible if the gene expression profile of at least 5 genes is analyzed and compared with the reference expression profiles, but the reliability is further increased the more genes are examined from the subgroup.
  • the first reference gene expression profile be obtained from those patients who do not relapse six months after completing platinum-based chemotherapy (platinum-sensitive patients), or if the second reference expression profile was obtained from those patients within six Suffer recurrence months after completion of platinum-based chemotherapy (platinum-resistant patients).
  • This measure has the advantage that reference gene expression profiles are established, which are based on generally accepted guidelines, such as those issued by the German Society for Gynecology and Obstetrics e.V. to assess whether a patient is platinum-sensitive or platinum-resistant. This measure additionally ensures that a correct classification of the patient to be examined takes place.
  • the number of platinum-sensitive patients substantially corresponds to the number of platinum-resistant patients. This measure ensures that meaningful and above all comparable reference gene expression profiles can be established.
  • the classification of the patient to be examined is increased in its accuracy again. In contrast, for example, the reference expression profile used by Helleman et al. (Supra) is not balanced and the associated classification method is inaccurate.
  • the authors examined 19 platinum-sensitive patients, but only 5 platinum-resistant patients.
  • the biological sample has tumor tissue, preferably derived from an ovarian carcinoma.
  • This measure has the advantage that the classification method according to the invention enables the conditions for a targeted therapy of a cancer patient, preferably a patient suffering from an ovarian carcinoma.
  • early detection of platinum resistance avoids the administration of toxic platinum and the associated burden on the patient and makes a decision for alternative therapy.
  • the biological sample has at least 50% tumor tissue.
  • This measure has the advantage that a particularly good and reliable classification of the patient to be examined is ensured.
  • gene expression activity is detected in tumor tissue in particular, which makes it possible to distinguish between platinum-sensitive patients and platinum-resistant patients.
  • the inventive method is modified such that its implementation is not immediately after the removal of the biological sample has to be done. Rather, the removed biological sample can be frozen and thus preserved and carried out the implementation of the method according to the invention in a special laboratory equipped for this purpose, to which the preserved sample is überschreibt.
  • cryopreserved tissue is as suitable for classification as "fresh" biological tissue taken just prior to processing.
  • a "support vector machine” represents a classifier.
  • An SVM subdivides a set of objects, for example genes or patients to be examined, into two classes so that the widest possible area remains free of objects around the class boundary.
  • the SVM is a mathematical pattern recognition technique that is implemented in computer programs, and the basis for building an SVM is a set of training objects, each of which is known to which class it belongs, for example, a set of patients who Each object is represented by a vector in a vector space, and the task of the SVM is to fit into this space a multidimensional hyperplane that acts as the interface and the training objects divides into two classes The distance of the vectors closest to the hyperplane to the hypereb ene is maximized. This wide, empty room should later ensure that even objects that do not correspond exactly to the training objects are classified as reliably as possible.
  • a class prediction can then be made on the basis of the expression profile of at least one of the 55 genes identified by the inventors, by means of which a vector, which represents the gene expression profile of a patient being examined, on one or the other side of the hyperplane is arranged, depending on to which reference gene expression profile greater similarities exist.
  • This makes it possible to classify a patient in platinum-sensitive or platinum-resistant.
  • the mathematical method of SVM is described, for example, in Burges CJ. C. (supra) and Perez-Diaz et al. (Supra). The content of these publications is incorporated by reference into the description.
  • step (2) of the classification method according to the invention comprises the following steps:
  • RNA transcripts Hybridization of the RNA transcripts to a biochip having at least those nucleic acid molecules which are hybridizable with RNA transcripts of the genes of the subgroup
  • This procedure has the advantage that measures which in themselves belong to the routine of a molecular biologist can be taken, can be carried out in molecular biological laboratories without great effort and ensure a reliable determination of the gene expression profile of the biological sample. A correct classification of the patient is thus ensured.
  • a preferred biochip is the "Human-6 v2 Expression BeadChip" from Illumina.
  • biochip with which the expression of more than 48,000 transcripts or genes of humans can be examined.
  • the chip is characterized by its high sensitivity, selectivity and measurement precision. Furthermore, only small amounts of biological material or RNA required to perform gene expression analysis. It is understood that other biochips are also suitable which have such nucleic acid molecules with which the transcripts of at least one gene, preferably of all 55 identified genes of the subgroup, are hybridisable.
  • a further subject matter of the present invention relates to a method for identifying informative genes in order to be able to classify a patient as platinum-sensitive or platinum-resistant, which comprises the following steps:
  • This method differs from the identification methods known in the art in that only those patients were used to obtain informative genes, which are classified as platinum-sensitive or platinum-resistant according to generally accepted guidelines.
  • a corresponding classification is, for example, also by the German Society of Gynecology and Obstetrics eV in the form of a "recommendation for diagnostics and diagnostics Therapy of malignant ovarian tumors ", as of September 2006, see the website at http://www.dggg.de/leitlinien2006/pdf-2006/2-onko-gyn/2/2- 5a-ovarialkarzinom-kurz-pdf.
  • the number of platinum-sensitive patients essentially corresponds to the number of platinum-resistant patients.
  • the biological samples have tumor tissue, preferably derived from an ovarian carcinoma.
  • the inventors have found that the identification method according to the invention can identify particularly well those informative genes which enable a distinction to be made between platinum-sensitive ovarian carcinoma patients and platinum-resistant ovarian carcinoma patients.
  • the identification method according to the invention is therefore particularly suitable for the classification of tumor patients.
  • the biological samples have at least 50% tumor tissue, which can be provided preferably also in cryopreserved form. This measure ensures that reliable informative genes are identifiable. Thus, such genes are suitable as "gene predictors", which are expressed differently in tumors of platinum-sensitive and platinum-resistant patients. Therefore, using only those biological samples that have at least 50% tumor tissue reliably leads to the identification of informative genes.
  • the inventors have found that not only "fresh" tumor tissue is suitable for the identification of informative genes by the method of the invention, but equally cryopreserved tissue.
  • the method can therefore be carried out in any molecular biological laboratory, which is not necessarily in close proximity to a clinic in which the patient to be examined, the tissue sample is removed. This can rather be frozen and preserved and sent to the examination laboratory.
  • step (3) is carried out using a support vector machine (SVM).
  • SVM support vector machine
  • step (2) comprises the following steps:
  • RNA transcripts 2.2 Transcription of the isolated RNA into complementary DNA (cDNA), 2.3 / nv / rro transcription of the cDNA to obtain RNA transcripts,
  • RNA transcripts were labeled with a detectable fluorescent marker.
  • the RNA transcripts were hybridized with a "Human 6 v2 Expression BeadChip" from Illumina. The result of the subsequent microarray analysis is shown in FIG.
  • the predictive power of the gene predictor set was verified from 18 samples derived from cisplatin-resistant ovarian cancer patients. The result is shown in Table 2.
  • FIG. 2 shows the result of a principal component analysis ("PCA") of the gene expression data with the overall data set (A) and the data of the "gene predictor set” from the 55 identified genes (B). Each point corresponds to a data set (array). Resistant samples are white, sensitive black.
  • the PCA with the unfiltered data set does not allow a clear distinction between cisplatin-sensitive and resistant patients, whereas the 55 genes of the "gene predictor set” allow a clear separation of the two groups of patents; see. Partial picture (B).

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Abstract

L'invention concerne un procédé servant à classer un patient comme sensible ou résistant au platine, l'utilisation du profil d'expression d'un sous-groupe de gènes pour classer un patient comme sensible ou résistant au platine, ainsi qu'un procédé pour l'identification de gènes informatifs permettant de classer un patient comme sensible ou résistant au platine.
PCT/EP2008/005965 2007-07-27 2008-07-21 Détection de la résistance au platine WO2009015799A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007036404.2 2007-07-27
DE200710036404 DE102007036404A1 (de) 2007-07-27 2007-07-27 Nachweis der Platinresistenz

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WO2009015799A2 true WO2009015799A2 (fr) 2009-02-05
WO2009015799A3 WO2009015799A3 (fr) 2009-06-11

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060019268A1 (en) * 2004-03-26 2006-01-26 Research Development Foundation Molecular markers of cisplatin resistance in cancer and uses thereof
US20060094012A1 (en) * 2002-07-31 2006-05-04 University Of Southern California Polymorphisms for predicting disease and treatment outcome

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060094012A1 (en) * 2002-07-31 2006-05-04 University Of Southern California Polymorphisms for predicting disease and treatment outcome
US20060019268A1 (en) * 2004-03-26 2006-01-26 Research Development Foundation Molecular markers of cisplatin resistance in cancer and uses thereof

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
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BERNARDINI M ET AL: "HIGH-RESOLUTION MAPPING OF GENOMIC IMBALANCE AND IDENTIFICATION OF GENE EXPRESSION PROFILES ASSOCAITED WITH DIFFERENTIAL CHEMOTHERAPY RESPONSE IN SEROUS EPITHELIAL OVARIAN CANCER" NEOPLASIA, DOYMA, BARCELONA, ES, Bd. 7, Nr. 6, 1. Juni 2005 (2005-06-01), Seiten 603-613, XP008068059 ISSN: 0212-9787 *
CHEN Z ET AL: "CORRELATION OF CISPLATIN SENSITIVITY WITH DIFFERENTIAL ALTERATION OF EGFR EXPRESSION IN HEAD AND NECK CANCER CELLS" ANTICANCER RESEARCH, HELENIC ANTICANCER INSTITUTE, ATHENS, Bd. 20, Nr. 2A, 1. März 2000 (2000-03-01), Seiten 899-902, XP009012770 ISSN: 0250-7005 *
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DE SMET F ET AL: "Predicting the clinical behavior of ovarian cancer from gene expression profiles." INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER : OFFICIAL JOURNAL OF THE INTERNATIONAL GYNECOLOGICAL CANCER SOCIETY 2006 JAN-FEB, Bd. 16 Suppl 1, Januar 2006 (2006-01), Seiten 147-151, XP002508552 ISSN: 1048-891X *
DRESSMAN HOLLY K ET AL: "An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer." JOURNAL OF CLINICAL ONCOLOGY : OFFICIAL JOURNAL OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY 10 FEB 2007, Bd. 25, Nr. 5, 10. Februar 2007 (2007-02-10), Seiten 517-525, XP002519673 ISSN: 1527-7755 *
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HELLEMAN JOZIEN ET AL: "Molecular profiling of platinum resistant ovarian cancer." INTERNATIONAL JOURNAL OF CANCER. JOURNAL INTERNATIONAL DU CANCER 15 APR 2006, Bd. 118, Nr. 8, 15. April 2006 (2006-04-15), Seiten 1963-1971, XP002519674 ISSN: 0020-7136 *
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MACLEOD KENNETH ET AL: "Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer" CANCER RESEARCH, Bd. 65, Nr. 15, August 2005 (2005-08), Seiten 6789-6800, XP002519751 ISSN: 0008-5472 *
PETERS DAVID ET AL: "Genome-wide transcriptional analysis of carboplatin response in chemosensitive and chemoresistant ovarian cancer cells." MOLECULAR CANCER THERAPEUTICS OCT 2005, Bd. 4, Nr. 10, Oktober 2005 (2005-10), Seiten 1605-1616, XP002519675 ISSN: 1535-7163 *
RICHARDSON ET AL: "Drug resistance in ovarian cancer: The emerging importance of gene transcription and spatio-temporal regulation of resistance" DRUG RESISTANCE UPDATES, CHURCHILL LIVINGSTONE, EDINBURGH, GB, Bd. 8, Nr. 5, 1. Oktober 2005 (2005-10-01), Seiten 311-321, XP005182400 ISSN: 1368-7646 *
ROBERTS D ET AL: "Identification of genes associated with platinum drug sensitivity and resistance in human ovarian cancer cells" BRITISH JOURNAL OF CANCER, Bd. 92, Nr. 6, 28. März 2005 (2005-03-28), Seiten 1149-1158, XP002519671 ISSN: 0007-0920 *
TAKEUCHI ET AL: "Cloning and characterization of DPPL1 and DPPL2, representatives of a novel type of mammalian phosphatidate phosphatase" GENE, ELSEVIER, AMSTERDAM, NL, Bd. 399, Nr. 2, 2. Juni 2007 (2007-06-02), Seiten 174-180, XP022190607 ISSN: 0378-1119 *

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