We will address a hitherto under-investigated aspect of individual differences in tumor response to chemotherapy by cytotoxic drugs - their determination by specific tumor chemotherapy response (Tctr) germline genes and investigate the potential to use them as response predictors. While cytotoxic drugs remain a mainstay and a critical component of most cancer therapies, such drugs generally achieve a measurable therapeutic effect in less than a half of patients. The lack of effective predictors of the individal tumor responsiveness results in a large proportion of patients suffering severe and sometimes lifelong toxic side effects without any therapeutic benefits. Moreover, during the administration of an ineffective drug the tumor continues to grow, so that the subsequent line of treatment, even of the second drug is effective, cannot achieve the same effect as with a smaller tumor, with the ensuing worse prognosis. Therefore the unpredictability of tumor responses to cytotoxic treatments represents an enormous barrier to successful cancer care. Numerous searches of a correlation between somatic alterations and response to therapy in tumors, tumor xenografts, or tumor cell lines did not yet result in development of reliable predictors of response to therapy. Similarly, candidate-gene strategies attempting to correlate polymorphic variants of genes involved in transport or processing of such drugs or DNA repair did not yet reveal genes with a significant predictor capacity. We observed a significant difference in response of lung tumors to irinotecan between two related mouse strains, CcS-2 (responder) and CcS-9 (non-responder), with the number of tumors after treatment decreasing by 50% in CcS-2 but remaining the same as in untreated mice in CcS-9. In this project we will test the hypothesis that this strain difference is due to presence of one or more tumor chemotherapy response (Tctr) genes in CcS-2, whose alleles in CcS-9 are inactive. We will test in a linkage study whether the putative Tctr genes can be indeed demonstrated as genuine germ-line genes that are located in specific chromosomal regions. A positive result will provide a proof of principle for Tctr genes and will allow to identify them in mice and their homologies in humans.
We propose to develop a novel way to determine in advance whether individual cancer patients will benefit from a therapy with a certain anti-cancer drug, or whether they should receive another drug, because their tumor is not likely to be suppressed by the drug considered as the first. This is exceptionally important, because presently a prediction whether a drug will be beneficial or whether the tumor will grow in spite of treatment is not possible, so many patients suffer toxic effects of anti-cancer drugs without deriving any benefit from them. The specific advantage of the method we propose is that it is based not only on the current knowledge of pharmacology of anti-cancer drugs, but can discover also reliable predictive factors that are based on novel mechanisms.