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：
9816429
负责人：
Michael Hemann
金额：
$ 34.02万
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/9816429
关键词：
ABL1 gene Acute Admixture Affect Aftercare B-Cell Acute Lymphoblastic Leukemia B-Cell Leukemia Biochemical Bypass Cancer Patient Cancer Remission Cells Chronic Myeloid Leukemia Clinic Clinical Clone Cells Combined Modality Therapy Complex Computer Simulation 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 Lead 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 Pharmacology Population Race Recurrent disease Refractory Relapse Residual Tumors Resistance Retinoic Acid Receptor Route Running Solid Therapeutic Therapeutic Intervention Time Transplantation Treatment Protocols Tretinoin Validation Work arm bcr-abl Fusion Proteins cancer therapy cancer type chemical genetics crizotinib drug development effective therapy experimental study genetic profiling inhibitor/antagonist leukemia melanoma mouse model neoplastic cell optimal treatments pre-clinical preclinical study preempt pressure resistance mechanism response small molecule small molecule inhibitor targeted agent targeted cancer therapy targeted treatment treatment response treatment strategy 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承担能力提供耐用诅咒的基本障碍。随着目标的近期和临床使用，这个问题变得越来越明显治疗学。某些白血病，黑色素瘤和半隔类肺肺肺部中未经预科的肿瘤回归，肿瘤不可避免地复发为化学浪费在某些情况下，有两年的治疗方法。各种机制或“进化轨迹”可以导致对前线的不同形式疗法和这些机制中的每一个都需要第二代疗法。代表靶向治疗剂的当前现实，在其中我们用剂治疗复发的肿瘤该目标是抗药性状态，创造了不可思议的抗药性武器竞赛实际上，疗法通常无法产生长期的癌症缓解或疾病管理。慢性粒细胞性白血病中只有BCR-ABL抑制剂始终长期疼痛癌症的恢复。白血病，在抗靶向治疗的抗性演变中，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抗性和消除残留疾病的抗性和消除残留疾病与许多其他癌症类型有关。 BCR-ABL+白血病和ALK驱动的肺部的侧支敏感性。临时侧支灵敏度如何解释为靶向进化的设置抗药性的轨迹。先发制人的耐药性，但也启发了结合策略促进耐用的方法治疗反应。