Renal cell carcinoma (RCC) is the third most common malignancy of the genitourinary system and corresponds to 2-3% of all human malignancies. Surgical resection is the most effective treatment for patients with localized RCC tumors, but such treatment for patients with advanced-stage RCC is not satisfactory. Although some biomedical therapies have been reported to show ˜20% response rate, they often cause severe adverse reactions and do not generally improve patients' survival. Among patients who have surgical treatment, approximately 25-30% relapse after surgery (Ljungberg B., Alamdari F. I., Rasmuson T. & Roos G. Follow-up guidelines for nonmetastatic renal cell carcinoma based on the occurrence of metastases after radical nephrectomy. BJU Int. 84, 405-411 (1999); Levy D A., Slaton J W., Swanson D A. & Dinney C P. Stage specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma. J Urol. 159, 1163-1167 (1998)). Tumor stage and surgical respectability are the most important prognostic factors for RCC; however, to date, little is known of the underlying molecular mechanisms that influence this variety in prognoses.
RCC tumors can be subdivided on the basis of histological features into clear cell (80%), papillary (˜10%), chromophobe (<5%), granular, spindle and cyst-associated carcinomas (5-15%). Each of these histological subtypes shows unique clinical behavior, with clear-cell and granular types tending to show more aggressive clinical phenotypes. Studies designed to reveal mechanisms of carcinogenesis have already facilitated the identification of molecular targets for certain anti-tumor agents. For example, inhibitors of farnesyltransferase (FTIs), which were originally developed to inhibit the growth-signaling pathway related to Ras, whose activation depends on post-translational farnesylation, have been shown to be effective in treating Ras-dependent tumors in animal models (He et al., Cell 99:335-45 (1999)). Similarly, clinical trials on humans using a combination of anti-cancer drugs and the anti-HER2 monoclonal antibody, trastuzumab, with the aim of antagonizing the proto-oncogene receptor HER2/neu, have resulted in improved clinical response and overall survival of breast-cancer patients (Lin et al., Cancer Res 61:6345-9 (2001)). Finally, a tyrosine kinase inhibitor, STI-571, which selectively inactivates bcr-abl fusion proteins, has been developed to treat chronic myelogenous leukemias, wherein constitutive activation of bcr-abl tyrosine kinase plays a crucial role in the transformation of leukocytes. Agents of these kinds are designed to suppress oncogenic activity of specific gene products (Fujita et al., Cancer Res 61:7722-6 (2001)). Accordingly, it is apparent that gene products commonly up-regulated in cancerous cells may serve as potential targets for developing novel anti-cancer agents.
It has been further demonstrated that CD8+ cytotoxic T lymphocytes (CTLs) recognize epitope peptides derived from tumor-associated antigens (TAAs) presented on the MHC Class I molecule, and lyse tumor cells. Since the discovery of the MAGE family as the first examples of TAAs, many other TAAs have been discovered using immunological approaches (Boon, Int J Cancer 54: 177-80 (1993); Boon and van der Bruggen, J Exp Med 183: 725-9 (1996); van der Bruggen et al., Science 254: 1643-7 (1991); Brichard et al., J Exp Med 178: 489-95 (1993); Kawakami et al., J Exp Med 180: 347-52 (1994)). Some of the newly discovered TAAs are currently undergoing clinical development as targets of immunotherapy. TAAs discovered so far include MAGE (van der Bruggen et al., Science 254: 1643-7 (1991)), gp100 (Kawakami et al., J Exp Med 180: 347-52 (1994)), SART (Shichijo et al., J Exp Med 187: 277-88 (1998)), and NY-ESO-1 (Chen et al., Proc Natl Acad Sci USA 94: 1914-8 (1997)). On the other hand, gene products demonstrated to be specifically over-expressed in tumor cells have been shown to be recognized as targets inducing cellular immune responses. Such gene products include p53 (Umano et al., Brit J Cancer 84: 1052-7 (2001)), HER2/neu (Tanaka et al., Brit J Cancer 84: 94-9 (2001)), CEA (Nukaya et al., Int J Cancer 80: 92-7 (1999)), and so on.
In spite of significant progress in basic and clinical research concerning TAAs (Rosenbeg et al., Nature Med 4: 321-7 (1998); Mukherji et al., Proc Natl Acad Sci USA 92: 8078-82 (1995); Hu et al., Cancer Res 56: 2479-83 (1996)), only limited number of candidate TAAs for the treatment of adenocarcinomas, including colorectal cancer, are currently available. TAAs abundantly expressed in cancer cells yet whose expression is restricted to cancer cells would be promising candidates as immunotherapeutic targets. Further, identification of new TAAs inducing potent and specific antitumor immune responses is expected to encourage clinical use of peptide vaccination strategies for various types of cancer (Boon and can der Bruggen, J Exp Med 183: 725-9 (1996); van der Bruggen et al., Science 254: 1643-7 (1991); Brichard et al., J Exp Med 178: 489-95 (1993); Kawakami et al., J Exp Med 180: 347-52 (1994); Shichijo et al., J Exp Med 187: 277-88 (1998); Chen et al., Proc Natl Acad Sci USA 94: 1914-8 (1997); Harris, J Natl Cancer Inst 88: 1442-5 (1996); Butterfield et al., Cancer Res 59: 3134-42 (1999); Vissers et al., Cancer Res 59: 5554-9 (1999); van der Burg et al., J Immunol 156: 3308-14 (1996); Tanaka et al., Cancer Res 57: 4465-8 (1997); Fujie et al., Int J Cancer 80: 169-72 (1999); Kikuchi et al., Int J Cancer 81: 459-66 (1999); Oiso et al., Int J Cancer 81: 387-94 (1999)).
It has been repeatedly reported that peptide-stimulated peripheral blood mononuclear cells (PBMCs) from certain healthy donors produce significant levels of IFN-γ in response to the peptide, but rarely exert cytotoxicity against tumor cells in an HLA-A24 or -A0201 restricted manner in 51Cr-release assays (Kawano et al., Cancer Res 60: 3550-8 (2000); Nishizaka et al., Cancer Res 60: 4830-7 (2000); Tamura et al., Jpn J Cancer Res 92: 762-7 (2001)). However, both HLA-A24 and HLA-A0201 are popular HLA alleles in the Japanese, as well as the Caucasian populations (Date et al., Tissue Antigens 47: 93-101 (1996); Kondo et al., J Immunol 155: 4307-12 (1995); Kubo et al., J Immunol 152: 3913-24 (1994); Imanishi et al., Proceeding of the eleventh International Hictocompatibility Workshop and Conference Oxford University Press, Oxford, 1065 (1992); Williams et al., Tissue Antigen 49: 129 (1997)). Thus, antigenic peptides of carcinomas presented by these HLAs may be especially useful for the treatment of carcinomas among Japanese and Caucasians. Further, it is known that the induction of low-affinity CTL in vitro usually results from the use of peptide at a high concentration, generating a high level of specific peptide/MHC complexes on antigen presenting cells (APCs), which will effectively activate these CTL (Alexander-Miller et al., Proc Natl Acad Sci USA 93: 4102-7 (1996)).
A hereditary cancer syndrome that sometimes involves the kidney, von Hippel-Lindau disease, results from germline mutations in the VHL gene (Latif F., Tory K., Gnarra J., Yao M., Duh F M., Orcutt M L., Stackhouse T., Kuzmin I., Modi W., Geil L., et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 260, 1317-20 (1993)). VHL is often inactivated in RCCs as well. Under physiological conditions, mutations or deletions of VHL lead to aberrant accumulation of the HIF1 protein due to dysfunction of ubiquitination machinery; in turn, accumulated HIF1 evokes the constitutive expression of downstream genes associated with growth and development of tumor cells. For example, Denko et al. demonstrated that expression of HIG2 is regulated by HIF1 under the hypoxic condition using the cells established from HIF1 deficient mouse (Denko N. et al., Epigenetic regulation of gene expression in cervical cancer cells by the tumor microenvironment. Clin Cancer Res. 6, 480-487 (2000) and on the worldwide web at 171.65.6.67/Hypoxia/outline%20for %20hig2.htm). HIF1 is composed of two subunits, HIF1α and HIF1β3. HIF1α is the oxygen-regulated component that determines HIF1 activity, and is rapidly degraded via ubiquitin-proteasome pathway under normoxic conditions.
To date, some genes that might be useful for prediction of prognosis or for classification of RCCs have been identified by cluster analysis (Takahashi M., Rhodes D R, Furge K A., Kanayama H., Kagawa S., Haab B B., Teh B T. Gene expression profiling of clear cell renal cell carcinoma: gene identification and prognostic classification. Proc Natl Acad. Sci. 98, 9754-9759 (2001); Skubitz K M., Skubitz A P. Differential gene expression in renal-cell cancer. J Lab Clin Med. 140, 52-64 (2002)). In an effort to understand the carcinogenic mechanisms associated with RCC and identify potential targets for developing novel anti-cancer agents for RCC, the present inventors performed large scale analyses of gene expression profiles of tumors of the predominant type, clear cell carcinoma.
USPTO Backgrounds
USPTO Backgrounds