Identifying and targeting evolutionary trajectories in cancer

项目总结/摘要 肿瘤演变是为癌症患者提供持久治疗的根本障碍。 随着靶向药物的最近和临床使用， 治疗学虽然促癌基因的小分子抑制剂已经导致了 在某些白血病、黑色素瘤和非小细胞肺癌中， 这些肿瘤不可避免地作为化疗难治性（对于初始治疗）恶性肿瘤复发， 一年或两年的初步治疗。在某些情况下，存在针对耐药性疾病的疗法。然而， 不同的机制或“进化轨迹”可能导致对前线的不同形式的抵抗， 这些机制中的每一种都可能需要不同的第二代疗法。这 代表了靶向治疗的现状，我们用药物治疗复发性肿瘤， 针对耐药国家，造成一场无法获胜的抵抗军备竞赛。因此，现代 治疗通常不能产生延长的癌症缓解或疾病控制。事实上， 只有BCR-ABL抑制剂在慢性粒细胞性白血病中始终实现了长期 癌症缓解我们最近发现了一种“时间侧支敏感性”的现象， 白血病，其中在对靶向治疗剂的抗性的演变中的不同中间阶段 存在利用来自正交药物类别的小分子的漏洞。的 这些进化弱点的存在为我们提供了一种阻止潜在途径的手段， 抵抗力和消除一线治疗后的残留疾病。我们认为这种现象 与许多其他癌症类型有关。在这里，我们建议描述时间的机制， BCR-ABL+白血病和ALK驱动的肺癌中的侧支敏感性。我们还计划检查 如何在临床前环境中利用时间侧支敏感性， 走向抗药性的轨迹我们认为，这项工作不仅将确定战略， 先发制人的耐药性，但也揭示了如何联合收割机这些战略，以促进持久的 治疗反应。

Project Summary/Abstract Tumor evolution represents the fundamental obstacle to providing durable cures for cancer patients. This problem has become increasingly apparent with the recent and clinical use of targeted therapeutics. While small molecule inhibitors of cancer-promoting oncogenes have led to unprecedented tumor regression in some leukemias, melanomas and non-small cell lung cancers, these tumors inevitably relapse as chemorefractory (to the initial therapeutic) malignancies within a year or two of initial treatment. In some cases, therapies exist to target drug resistant disease. Yet, diverse mechanisms or “evolutionary trajectories” can lead to distinct forms of resistance to front-line therapies, and each of these mechanisms may require a distinct second generation therapy. This represents the current reality of targeted therapeutics, in which we treat relapsed tumors with agents that target the drug resistant state, creating an unwinnable resistance arms race. Thus, modern therapies have generally failed to yield prolongued cancer remission or disease management. In fact, only BCR-ABL inhibitors in Chronic Myelogenous Leukemia have consistently achieved long-term cancer remissions. We recently discovered a phenomenon of “temporal collateral sensitivity” in leukemia, whereby distinct intermediate stages in the evolution of resistance to targeted therapeutics present vulnerabilities for exploitation using small molecules from orthogonal drug classes. The existence of these evolutionary vulnerabilities provides us with a means of blocking potential routes to resistance and eradicating residual disease following front-line therapy. We believe this phenomenon is relevant to many other cancer types. Here, we propose to characterize the mechanism of temporal collateral sensitivity in BCR-ABL+ leukemia and ALK-driven lung cancer. We also plan to examine how temporal collateral sensitivity can be exploited in preclinical settings to target evolutionary trajectories towards drug resistance. We believe that this work will not only identify strategies for preempt drug resistance, but also reveal ways to combine these strategies to promote durable therapeutic responses.