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WO 2009/080437 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 2 July 2009 (02.07.2009) PCT WO 2009/080437 Al (51) International Patent Classification: Copenhagen N (DK). LITMAN, Thomas [DK/DK]; C12Q 1/68 (2006.01) Rosen AlIe 8, Hareskovby, DK-3500 Vaeløse (DK). M0LLER, Søren [DK/DK]; Ved Furesøen 9, DK-2840 (21) International Application Number: Holte (DK). PCT/EP2008/066239 (74) Agent: INSPICOS A/S; P.O. Box 45, Kogle AlIe 2, (22) International Filing Date: DK-2970 Hørsholm (DK). 26 November 2008 (26.1 1.2008) (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, (30) Priority Data: EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, PA 2007 01843 2 1 December 2007 (21.12.2007) DK IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, 61/015,797 21 December 2007 (21.12.2007) US LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, PA 2008 00535 11 April 2008 (11.04.2008) DK MX, MY,MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, (71) Applicant (for all designated States except US): EXIQON RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TJ, A/S [DK/DK]; Skelstedet 16, DK-2950 VEDB^K (DK). TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (72) Inventors; and ZW (75) Inventors/Applicants (for US only): KONGSBAK, Lars (84) Designated States (unless otherwise indicated, for every [DK/DK]; Vaengestien 2A, DK-2840 HoIte (DK). S0K- kind of regional protection available): ARIPO (BW, GH, ILDE, RaIf [DK/DK]; Haraldsgade 3, 2.th., DK-2200 GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, [Continued on next page] (54) Title: MICRO-RNA BASED DRUG RESISTANCE ANALYSIS METHOD (57) Abstract: The invention relates Figure 8 to the analysis of samples, such as cancer samples, isolated from patients, to determine or predict the phenotype of the patient or disease, such as cancer, with respect to the resistance or susceptibility of the patient or disease to treatment, such as cancer treatment. The analysis is based on determination of the abundance of microRNAs which are associated with resistance against the treatment, such as extreme drug resistance (EDR). ιR_1 965 ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Published: European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, — with international search report FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, — with sequence listing part of description published sepa- NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, rately in electronicform and available upon requestfrom CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). the International Bureau MICRO-RNA BASED DRUG RESISTANCE ANALYSIS METHOD FIELD O F THE INVENTION The invention relates t o the analysis of samples, such as disease samples, such as cancer samples, isolated from patients to determine or predict the phenotype of the patient or disease, such as cancer, with respect to the resistance or susceptibility of the patient or disease to treatment, such as cancer treatment. The analysis is based on determination of the abundance of microRNAs which are associated with resistance against the treatment, such as extreme drug resistance (EDR). BACKGROUND TO THE INVENTION MicroRNAs (miRNAs) have rapidly emerged as an important class of short endogenous RNAs that act as post-transcriptional regulators of gene expression by base-pairing with their target mRNAs. microRNAs are differentially expressed in human cancers and a series of recent publication show that microRNA classify human cancers; in some cases improvement over mRNA classification is observed. Indeed, in a series of publications during recent years, it has become clear that microRNAs are extensively involved in cancer pathogenesis, and microRNA has been shown to be differentially expressed in a number of cancers (Breast cancer: Iorio et al Cancer Res 2005; 65: 7065. Lung cancer: Yanaihara et al Cell Science 2006; 9 : 189-198. Chronic lymphocytic leukaemia (CLL): GaNn et al PNAS, 2004 101(32): 11755-11760. Colon cancer: Cummins et al PNAS 2006, 103 (10):3687-3692. Prostate cancer: Volinia et al PNAS 2006; 103: 2257). Indeed, in a landmark paper Lu et al (Nature 2005; 435:834-838) demonstrated that differential expression of microRNA in multiple cancers types, and that signatures based on approximately 200 microRNAs improve classification of poorly differentiated cancers over mRNA profiles. The expected complexity of the "microRNA'nome" is far smaller than the human transcriptome with the total number of microRNAs being approximately limited t o between 800 and 1000. Therefore, a microRNA cancer signature can be predicted t o include from 5 - 20 microRNAs, suggesting that microRNA based theranostics will be of limited complexity and far more robust than mRNA profiles. PCT/EP2007/061210 and US 11/975,644, both hereby incorporated by reference, report on novel microRNAs which are associated with cancer, and detection probes based on the complement of the novel miRNA sequences, including LNA detection probes, for diagnostic use: Including the use of miRNA profiling for therapy outcome prediction, such as a prediction of the responsiveness of the cancer to chemotherapy and/or radiotherapy and/or the suitability of said cancer to hormone treatment, and such as the suitability of said cancer for removal by invasive surgery. In one embodiment, the therapy out come predication may be the prediction of the suitability of the treatment of the cancer to combined adjuvant therapy. The therapy may be herceptin, which is frequently used for the treatment of oestrogen receptor positive cancers (such as breast cancer). PCT/DK2005/000838, and US application 11/324,177, both hereby incorporated by reference, discloses methods for the detection of microRNAs (miRNAs) using oligonucleotides which comprise nucleotide analogues, such as locked nucletic acids (LNAs). WO2005/098029, hereby incorporated by reference, discloses a method using oligonucleotides for the detection, quantification, monitoring of expression of miRNA. It is suggested that the method can be used for determining the differences between nucleic acid samples from e.g. a cancer patient. The Sanger Institute publishes known miRNA sequences in the miRBase database (http://microrna.sanqer.ac.uk/sequences/index.shtml). To date there are 533 human miRNAs present in the miRBase database. The Extreme Drug Resistance (EDR®, Oncotech Inc.) assay is an in vitro test that measures the ability of pharmaceutical agents and other chemotherapies to stop cancer cells from dividing and growing - it has been reported that the assay identifies patients that will not respond to a particular cancer treatment with over 99% accuracy and is used to exclude agents unlikely to provide a therapeutic benefit in the treatment of cancer in an individual patient, as well as in providing information which can be used to select those agents which are likely to be clinically effective, resulting in improved response rates and prolonged survival of cancer patients. The EDR® assay method involves the isolation of fresh viable tumor tissue which is minced and digested with enzymes to disaggregate the tumor cells. The cells are then placed in soft agar to encourage cell proliferation before being exposed to the chemotherapeutic agents, typically for a period of five days and at an elevated dosage, during the latter period of drug exposure tritiated thymidine is added as a measure of cell proliferation. By comparing the level of label incorporated into drug treated and untreated controls, the degree of cell proliferation under the drug treatment is determined, and thereby the resistance phenotype of the cancer cells. Despite the effectiveness of the EDR® assay in identifying drug resistance tumours, the assay requires a relatively large amount of tumour tissue, and takes about 7 days to perform. There is therefore a need for improved drug resistance assays, which use less cancer tissue and may be performed in a shorter time period. The correlation of specific gene (mRNA) or protein expression or DNA copy number and the drug resistance phenotype has been used to assay drug resistance of individual tumour samples: US 2004/0214203 reports on methods for prognosis, diagnosis, staging and disease progression in human cancer patients related to expression of levels of a plurality of genes that are differentially expressed in chemotherapeutic drug resistant and drug sensitive tumour cells. US 2006/0160114 reports on methods for prognosis, diagnosis, staging and disease progression in human cancer patients related to expression of levels of one or a plurality of genes or genetic loci that are differentially deleted, amplified, expressed or amplified and over-expressed in chemotherapeutic drug resistant tumor cells. RELATED APPLICATIONS The following applications are hereby incorporated by reference PCT/EP2007/061210, US 11/975,644, and US provisional applications US 60/853,410 and US 60/900,081. SUMMARY O F THE INVENTION The invention is based upon the discovery that microRNA profiling of cancer cells or tissues may be used as an efficient, effective and rapid indicator of a drug resistance or drug susceptibility phenotype of cancer cells. This discovery illustrates that microRNA profiling may be used as a method of predicting the phenotype of a subject suffering from a disease, or or the phenotype of a sample or cell(s) obtained from said patient, which may, suitably consist or comprise of a sample of diseased tissue or cells, such as a cancer sample (or cell(s)), with respect to the resistance or susceptibility of the subject or sample or cell(s) to one or more treatments of the disease.
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