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Target Genes for the Diagnosis and Treatment of Cancer

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Target Genes for the Diagnosis and Treatment of Cancer Europäisches Patentamt *EP001369482A1* (19) European Patent Office Office européen des brevets (11) EP 1 369 482 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C12N 15/12, C07K 14/47, 10.12.2003 Bulletin 2003/50 C07K 16/18, C12N 5/10, A61K 31/00, A61K 38/00, (21) Application number: 02012705.6 A61K 48/00, A61P 35/00, (22) Date of filing: 07.06.2002 G01N 33/53 (84) Designated Contracting States: • Poustka, Annemarie AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU 69120 Heidelberg (DE) MC NL PT SE TR • Mollenhauer, Jan Designated Extension States: 69118 Heidelberg (DE) AL LT LV MK RO SI • Schadendorf, Dirk 68165 Mannheim (DE) (71) Applicant: Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts (74) Representative: Isenbruck, Günter, Dr. 69120 Heidelberg (DE) Isenbruck, Bösl, Hörschler, Wichmann, Huhn, Patentanwälte (72) Inventors: Theodor-Heuss-Anlage 12 • Wittig, Rainer 68165 Mannheim (DE) 69121 Heidelberg (DE) (54) Target genes for the diagnosis and treatment of cancer (57) The present invention relates to the identifica- tool to render drug-resistant cells drug-sensitive. In ad- tion and use of target genes for the detection and treat- dition, the present invention includes the polypeptides ment of drug-resistant tumor cells. The nucleic acids of encoded by the respective nucleic acids, expression the present invention exhibit a deregulated phenotype vectors harboring the nucleic acids, host cells for ex- when the tumor cells are subjected to cytostatic drugs, pression and methods for the diagnosis and treatment i.e. they are expressed in a higher or lower amount as of drug-resistant tumor cells. compared to parental drug-sensitive cancer cells. Thus, they can be used as a diagnostic and pharmaceutical EP 1 369 482 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 369 482 A1 2 Description polypeptides or immunogenic fragments thereof, which are deregulated in drug-resistant tumor cells in re- [0001] The present invention relates to the identifica- sponse to drug exposure as compared to the drug-sen- tion and use of target genes for the detection and treat- sitive parental cells, wherein said nucleic acids com- ment of drug-resistant tumor cells. 5 prise those genes which are disclosed by the following [0002] Cancer is the second major cause of death in complete and/or partial sequence identification num- Europe and Northern America. In view of the increasing bers: U63131, L11667, L48513, Z30093, X13293, number in cancer cases, any approach to improve cur- L26081, M14200, X91171, D23662, L28824, L12401, rent treatment methods is of important ethic, social and D10522, M94345, AF063228, M19267, AF009615, economic value. The effective cure of patients, though, 10 U92436, U59831, U19251, Z50781, X79550, is often difficult since many tumor cells develop a resist- AF035812, X63468, M22919, L19605, X06820, ance to anticancer drugs used for chemotherapy. The M33336, S74017, L11066, U59877, M19645, X92669, described phenotype, also termed drug resistance D16581, M81601, V00530, D29013, M29874, L13740, (DR), involves a variety of strategies that tumor cells use M60974, X79683, U84388, M95809, D49547, L06623, to evade the cytostatic effects of anticancer drugs. DR 15 D90209, J05428, K02770, X15880, X76771, X53280, is characterized by a decreased sensitivity of tumor cells M22760, U04520, L20298, Y14690, U13991, X06994, to the drug employed for chemotherapy and, often, also M22299, U44754, X58531, U84573, U11690, H45315, to a broad spectrum of further drugs with neither obvious M11717, X85106, D50310, W68277, R09223, U36798, structural homology nor common targets. Mechanisms J04164, R76702, AB000584, R97220, M22976, for DR include modifications in detoxification and DNA 20 AB023155, U79303, X67325, AB005047, AA410441, repair pathways, changes in cellular sites of drug se- U46499, AB021288, U31345, M54968, M65212, questration, decreases in drug-target affinity, synthesis J02611, X90858, U18728, M13755, H00952, H11608, of specific drug inhibitors within cells, and accelerated X15729, H57310, M64925, L18967, AK000917, removal or secretion of drugs. More recently, cellular NM_018330, U90878, X02492, U50648, U09510, drug resistance has been associated with alterations in 25 X01060, X57352, S45630, J04129, S40706, cell death pathways, a process known as apoptosis, but AF126743, NM_015894, NM_013451, AI624266, to date the molecular basis and exact mechanisms re- AL117608, NM_020182, NM_021216, AC007228, pos. main poorly understood. 66685-66811 (see Table 1). [0003] Acute or chronic exposure to cancer drugs pro- [0007] The present invention further includes deriva- duces an adaptive response in tumor cells, mainly 30 tives and fragments of any of said nucleic acids, provid- caused by an altered gene expression as compared to ed that their capacity to overcome the said drug resist- drug-sensitive cells. The altered gene expression found ance remains unaffected. The term derivative or frag- in various human tumors is often caused by the ampli- ment of the disclosed sequences refers to DNA se- fication, deletion, recombination, or other mutations of quences in which one or more nucleotides of the coding certain genes. Increased or decreased expression of 35 sequence can be substituted by one or more nucle- those target genes usually provide a selective advan- otides different from the original one(s), or DNA se- tage for the tumor cells and play therefore an important quences the nucleotide sequence of which is either ex- role for the pathogenesis and prognosis of DR in human tended, shortened, or both, on either the 5'-, or the 3'- cancer. or both ends, or in the center portion, provided that the [0004] Changes in gene expression in target cells can 40 function of the nucleic acids and their encoded proteins lead to an acquired resistant phenotype and can also remains unaffected. provide clues about intracellular targets essential for [0008] Furthermore, in the context of the present in- overcoming DR. From the foregoing, it becomes evident vention the term derivative or fragment refers to DNA that tumor cells which are resistant to anticancer drugs sequences that are complementary to the so-called an- due to the overexpression of particular genes may be 45 tisense strand of the disclosed nucleic acids. Hereinaf- rendered drug-sensitive and, thus, treatable if the re- ter, they will be further referred to as antisense oligonu- spective genes, RNAs, or proteins are specifically cleotides. knocked out, inhibited, or down-regulated. Similarly, [0009] The present differentially expressed nucleic drug resistance as a result of little or no expression of acids/genes can be identified by methods well known to particular genes may be overcome by supplementing 50 the person skilled in the art, including comparative PCR, the function of the underrepresented or missing gene. semi-quantitative RT-PCR, immunoscreening, South- [0005] The object of the present invention is to provide ern Blotting, Northern blotting, subtractive hybridization, target genes that are useful for the effective treatment representational difference analysis (RDA), serial anal- of tumor cells using anticancer drugs. ysis of gene expression (SAGE) and mRNA differential [0006] The present invention is directed to genes, 55 display (DD) methods performing a genome-wide scan which are differentially expressed in multiple drug-re- for differentially expressed genes using cDNA microar- sistant cells relative to drug-sensitive cells. Thus, the ray for hybridization studies. The latter represents the object is attained by nucleic acids encoding human preferred method of the present invention. 2 3 EP 1 369 482 A1 4 [0010] As used herein, "deregulated" means that the AAA35731, AAC41995, CAA82909, CAA31655, nucleic acids of the present invention are expressed ei- AAA65938, AAA52171, CAA62596, BAA04889, ther higher or lower in cells that were exposed to drugs AAA36526, NP_005563, BAA01392, AAA59570, with respect to cells that were not exposed to drugs. In AAC33443, AAA36771, AAC51766, AAC51182, a preferred embodiment of the present invention the 5 AAC50660, AAC52045, CAA90644, CAA56093, term is defined in that the single array spots represent- AAB88513, CAA45068, AAA59893, AAA19734, ing differentially expressed genes display expression CAA29968, AAB50921, AAB32188, NP_004125, ratios of at least 2.5 and 1:2.5 when using the UniGene AAB02832, AAA52614, CAA63356, BAA04013, Array, and expression ratios of at least 1.5 and 1:1.5 AAA61138, CAA23789, BAA06099, AAA52144, when using the drug-resistance subarray (see Materials 10 AAA36763, AAA35863, CAA56130, AAC50952, and Methods). AAA58399, BAA08495, AAA52342, BAA14234, [0011] As used hereinafter, the term "drug", which AAA36793, AAA36106, CAA33889, CAA54166, causes a deregulation of said nucleic acids molecules CAA37375, AAA99220, AAF66217, AAA02868, refers to so-called cytostatic drugs comprising (i) an- CAA75002, AAA62230, CAA30052, AAB02844, timetabolites, such as cytarabine, fludarabine, 5-fluoro- 15 AAC50358, CAA41418, AAB58363, AAA57004, 2'-deoxyuiridine, gemcitabine, hydroxyurea or meth- NP_003061, AAA52697, CAA59427, BAA08849, otrexate; (ii) DNA-fragmenting agents, such as bleomy- NP_002520, NP_000921, AAB18673, AAA35494, cin, (iii) DNA-crosslinking agents, such as chlorambucil, NP061885, BAA19151, AAA52133, BAA76782, cisplatin, fotemustine, cyclophosphamide or nitrogen AAB50227, CAA47739, BAA25922, NP_064696, mustard; (iv) intercalating agents such as adriamycin 20 BAA35182, AAB60371, AAB41942, AAA68927,
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