Identifying and targeting evolutionary trajectories in cancer

项目摘要/摘要 肿瘤进化是为癌症患者提供持久治疗的根本障碍。 随着靶向药物的近期和临床应用，这个问题变得越来越明显。 治疗学。而促癌基因的小分子抑制剂则导致了 在一些白血病、黑色素瘤和非小细胞肺癌中出现了前所未有的肿瘤消退， 这些肿瘤不可避免地在一年内复发为化疗难治(最初治疗)的恶性肿瘤 一到两年的初步治疗。在某些情况下，存在针对耐药疾病的治疗方法。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 这些疗法中的每一种都可能需要不同的第二代疗法。这 代表了当前靶向治疗的现实，在这种治疗中，我们用药物治疗复发的肿瘤 这些措施针对的是耐药州，造成了一场无法取胜的抵抗军备竞赛。因此，现代的 治疗通常不能产生延长癌症缓解或疾病控制的效果。事实上, 只有bcr-abl抑制剂在慢性粒细胞白血病中持续取得长期疗效 癌症缓解。我们最近发现了一种“时间附带敏感性”的现象 白血病，靶向治疗药物耐药性演变的不同中间阶段 存在使用来自正交药物类别的小分子进行开发的漏洞。这个 这些进化漏洞的存在为我们提供了一种阻止潜在路径的方法 抵抗和根除一线治疗后的残留病。我们相信这一现象 与许多其他癌症类型相关。在这里，我们建议刻画时间的机制 Bcr-abl+白血病和碱性磷酸酶驱动的肺癌的侧支敏感性。我们还计划检查 如何在临床前环境中利用时间侧枝敏感性来针对进化 抗药性的轨迹。我们相信，这项工作不仅将确定战略， 抢占抗药性，但也揭示了将这些策略结合起来促进耐用性的方法 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.