Identifying and targeting evolutionary trajectories in cancer

识别和瞄准癌症的进化轨迹

基本信息

批准号：
10670750
负责人：
Michael Hemann
金额：
$ 33.57万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-14 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670750
关键词：
ABL1 gene Acute Admixture Affect Aftercare B-Cell Acute Lymphoblastic Leukemia B-Cell Leukemia Biochemical Bypass Cancer Patient Cancer Remission Cells Chemicals Chronic Myeloid Leukemia Clinic Clinical Combined Modality Therapy Complex Computer Models Data Development Disease Disease Management Disease Resistance Disease remission Drug Targeting Drug resistance Engineering Epigenetic Process Evolution Generations Genetic Gleevec Hematopoietic Neoplasms Heterogeneity Human Hypersensitivity Leukemic Cell Malignant Neoplasms Malignant neoplasm of lung Modeling Modernization Mus Mutation Myeloid Leukemia Non-Small-Cell Lung Carcinoma Oncogenes Pathway interactions Patients Pharmaceutical Preparations Population Recurrent disease Refractory Relapse Residual Neoplasm Resistance Retinoic Acid Receptor Route Running Solid Therapeutic Therapeutic Intervention Time Transplantation Treatment Protocols Tretinoin Validation Work arms race bcr-abl Fusion Proteins cancer therapy cancer type crizotinib drug resistance development effective therapy experimental study genetic profiling inhibitor leukemia melanoma mouse model neoplastic cell novel therapeutic intervention optimal treatments patient derived xenograft model pharmacologic pre-clinical preclinical study preempt pressure resistance mechanism response small molecule small molecule inhibitor targeted agent targeted cancer therapy targeted treatment treatment response tumor tumor heterogeneity

项目摘要

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.

项目摘要/摘要肿瘤的演变代表了为癌症患者提供持久治疗方法的基本障碍。随着目标的近期和临床使用，这个问题变得越来越明显疗法。虽然促进癌症基因的小分子抑制剂已导致某些白血病，黑色素瘤和非小细胞肺癌的空前肿瘤回归，这些肿瘤不可避免地将其作为化学浪费（最初疗法）在初始治疗的年或两年。在某些情况下，存在靶向抗药性疾病的疗法。然而，各种机制或“进化轨迹”可以导致对前线的不同形式疗法以及这些机制中的每一种都可能需要独特的第二代疗法。代表了靶向疗法的当前现实，在该现实中，我们将其治疗带有药物的中继肿瘤该针对耐药状态，创造了不可分割的抵抗力武器竞赛。那，现代疗法通常无法产生长时间的癌症缓解或疾病治疗。实际上，慢性粒细胞性白血病中只有BCR-ABL抑制剂始终达到长期癌症减免。最近，我们发现了一种“暂时侧支灵敏度”现象白血病，抗靶向治疗的耐药性演变中不同的中间阶段目前使用正交药物类别的小分子进行剥削的漏洞。这这些进化脆弱性的存在为我们提供了阻止潜在路线的方法前线治疗后的抵抗和消除残留疾病。我们相信这种现象与许多其他癌症类型有关。在这里，我们建议表征临时机制 BCR-ABL+白血病和ALK驱动的肺癌中的侧支灵敏度。我们还计划检查如何在临床前环境中探索临时侧支灵敏度以靶向进化朝着耐药性的轨迹。我们认为，这项工作不仅会确定先发制人的耐药性，但也揭示了结合这些策略以促进耐用的方法治疗反应。