Genomic markers predicting tumor response to cytotoxic chemotherapy

预测肿瘤对细胞毒性化疗反应的基因组标记

• 批准号: 9188061
• 负责人: PETER DEMANT
• 金额: $ 8.58万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188061
• 关键词: Address; Adverse effects; Aftercare; Alleles; Antineoplastic Agents; Backcrossings; Cancer Patient; Candidate Disease Gene; Cells; Cytotoxic Chemotherapy; Cytotoxic agent; DNA Repair; Development; Enzymes; Ethylnitrosourea; Face; Gene Expression Profile; Genes; Genetic Polymorphism; Genome; Germ Lines; Human; Hybrids; Impairment; Individual; Individual Differences; Knowledge; Lead; Lung Neoplasms; Measurable; Methods; Minority; Mouse Strains; Mus; Names; Patients; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Predictive Factor; Production; Quality of life; Reaction; Regulation; Research; Risk; System; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Tumor Cell Line; base; cancer care; cancer cell; cancer therapy; chemotherapy; congenic; cytotoxic; experimental study; genetic variant; genomic biomarker; improved; improved outcome; ineffective therapies; irinotecan; novel; outcome forecast; personalized medicine; predicting response; predictive marker; public health relevance; response; targeted treatment; treatment response; tumor; tumor xenograft; uptake

 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.

 描述（由申请人提供）：我们将解决迄今为止尚未充分研究的肿瘤对细胞毒性药物化疗反应的个体差异的方面，即通过特定的“肿瘤化疗反应”（Tctr）种系基因来确定它们，并研究将它们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达到可测量的治疗效果。由于缺乏个体肿瘤反应性的有效预测因子，导致很大一部分患者遭受严重的、有时是终生的毒副作用，而没有任何治疗益处。此外，在施用无效药物期间，肿瘤继续生长，因此即使第二种药物有效，后续治疗也无法达到与较小肿瘤相同的效果，从而导致预后较差。因此，肿瘤对细胞毒性治疗的反应的不可预测性是成功癌症治疗的巨大障碍。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研究，但尚未开发出可靠的治疗反应预测因子。同样，候选基因策略试图将参与此类药物的运输或加工或 DNA 修复的基因的多态性变体关联起来，但尚未揭示具有显着预测能力的基因。我们观察到两种相关小鼠品系 CcS-2（有反应者）和 CcS-9（无反应者）之间肺部肿瘤对伊立替康的反应存在显着差异，CcS-2 中治疗后的肿瘤数量减少了 50%，但 CcS-9 中的肿瘤数量与未治疗的小鼠相同。在这个项目中，我们将测试这一假设，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，而 CcS-9 中的等位基因是不活跃的。我们将在连锁研究中测试推定的 Tctr 基因是否确实可以被证明是位于特定染色体区域的真正种系基因。积极的结果将为 Tctr 基因提供“原理证明”，并允许在小鼠中识别它们及其在人类中的同源性。