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未被研究的肿瘤对细胞毒性药物化疗反应的个体差异的一个方面--它们由特定的“肿瘤化疗反应”(Tctr)胚系基因决定，并研究它们作为反应预测因子的可能性。尽管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取得了可测量的治疗效果。缺乏对个体肿瘤反应的有效预测因素导致很大比例的患者遭受严重的、有时是终生的毒副作用，而没有任何治疗益处。此外，在服用无效药物期间，肿瘤继续生长，因此后续的治疗路线，即使第二种药物有效，也不能达到与较小肿瘤相同的效果，从而导致更差的预后。因此，肿瘤对细胞毒治疗反应的不可预测性是成功治疗癌症的巨大障碍。在肿瘤、肿瘤移植瘤或肿瘤细胞系中，对躯体改变和治疗反应之间的相关性进行了大量研究，但尚未形成可靠的治疗反应预测指标。同样，候选基因策略试图将参与此类药物运输或加工或DNA修复的基因的多态变体关联起来，但尚未发现具有显著预测能力的基因。我们观察到两个相关的小鼠品系CCS-2(有反应)和CCS-9(无反应)对伊立替康的反应有显著差异，治疗后CCS-2的肿瘤数量减少了50%，但CCS-9的肿瘤数量与未治疗的小鼠相同。在这个项目中，我们将检验一种假设，即这种菌株差异是由于CCS-2中存在一个或多个“肿瘤化疗反应”(Tctr)基因，其等位基因在CCS-9中处于非活跃状态。我们将在一项连锁研究中测试假定的Tctr基因是否真的可以被证明是位于特定染色体区域的真正的生殖系基因。阳性结果将为Tctr基因提供“原则证据”，并将允许在小鼠身上鉴定它们，并在人类中鉴定它们的同源性。

 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.