Genomic markers predicting tumor response to cytotoxic chemotherapy

 描述（由申请人提供）：我们将解决迄今为止尚未研究的肿瘤对细胞毒性药物化疗反应的个体差异方面-通过特定的"肿瘤化疗反应"（Tctr）生殖系基因确定，并研究将其用作反应预测因子的潜力。虽然细胞毒性药物仍然是大多数癌症治疗的支柱和关键组成部分，但此类药物通常在不到一半的患者中实现可测量的治疗效果。由于缺乏有效的预测个体肿瘤反应性的指标，导致很大比例的患者遭受严重的，有时是终身的毒副作用，而没有任何治疗益处。此外，在施用无效药物期间，肿瘤继续生长，使得后续治疗线，即使第二药物有效，也不能达到与较小肿瘤相同的效果，随之而来的是更差的预后。因此，肿瘤对细胞毒性治疗反应的不可预测性是成功治疗癌症的巨大障碍。对肿瘤、肿瘤异种移植物或肿瘤细胞系中体细胞改变与治疗反应之间的相关性进行了大量检索，但尚未开发出治疗反应的可靠预测因子。类似地，候选基因策略试图关联参与运输或加工此类药物或DNA修复的基因的多态性变体，但尚未发现具有显著预测能力的基因。我们观察到两种相关小鼠品系CcS-2（应答者）和CcS-9（非应答者）之间肺肿瘤对伊立替康的应答存在显著差异，CcS-2中治疗后肿瘤数量减少50%，但CcS-9中与未治疗小鼠保持相同。在这个项目中，我们将测试的假设，这种菌株的差异是由于存在一个或多个“肿瘤化疗反应”（Tctr）基因在CcS-2，其等位基因在CcS-9是无活性的。我们将在连锁研究中测试是否推定的Tctr基因确实可以被证明是真正的生殖系基因，位于特定的染色体区域。阳性结果将为Tctr基因提供“原理证明”，并将允许在小鼠中识别它们及其在人类中的同源性。

 DESCRIPTION (provided by applicant): 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.