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Functional identification of CLL drug response and resistance

CLL药物反应和耐药性的功能鉴定

基本信息

批准号：
10005159
负责人：
ANTHONY G LETAI
金额：
$ 30.54万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005159
关键词：
Aftercare Apoptosis Apoptotic Behavior Cell Survival Cells Chemical Evolution Chemicals Classification Clinical Combination Drug Therapy Combined Modality Therapy Data Set Dependence Disease Dissection Drug Combinations Drug Sensitization Epigenetic Process Evolution Exposure to Genetic Genome Genomics Goals Hour Institutes Laboratories Libraries Measurement Measures Methods Mining Molecular Outcome Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phenotype Relapse Reporting Resistance Sampling Sum Therapeutic Time anti-PD-1 base cancer cell chemotherapy clinically relevant cytotoxicity design drug discovery epigenome epigenomics fludarabine improved in vivo individual patient leukemia molecular marker neoplastic cell novel novel strategies novel therapeutics phenome prevent prospective relapse patients response screening small molecule transcriptome transcriptomics treatment strategy tumor

项目摘要

Project Summary: Despite impressive therapeutic advances in the treatment of CLL over the past decade, relapsed tumors that are often resistant to known therapies remain a problem. Understanding resistance and developing new treatment strategies will be necessary to turn CLL into a curable disease. With few notable exceptions, responses to chemotherapy typically occur through apoptosis, a form of programmed cell death. Our goal is to identify drugs that sensitize CLL cells to apoptosis, and to identify combinations of drugs that would prevent relapse. While chemical screening of conventional cytotoxicity is an attractive strategy to meet this goal, such an approach is impeded by the inability to reliably culture CLL cells for longer than 48 hours ex vivo. This ultimately reflects a technological gap in our ability to chemically perturb CLL ex vivo, and measure functional and clinically relevant phenotypes. Here, we will use a novel chemical screening approach called dynamic BH3 profiling (DBP), which enables functional measurements of chemically induced apoptotic changes, and requires only 6-24 hours of ex vivo culture, thereby maximizing molecular fidelity and tumor cell viability. Using a panel of over 2000 drugs, not only will we identify novel molecules that sensitize CLL cells for apoptosis, but we will also determine chemical apoptotic sensitivities that are lost or gained on relapse for individual patients. Drugs that uniquely sensitize only relapsed tumors present exciting opportunities for combination chemotherapy. Finally to understand mechanisms of apoptotic vulnerabilities in pre- and post-treatment samples, we will correlate our measurements of functional apoptotic responses with the large molecular datasets in Project 1 and 2 for at least 104 CLL patients. In sum, the successful identification of apoptotic sensitizing drugs in CLL, will not only advance our molecular understanding of CLL, but could result in truly novel therapeutic options.

项目摘要：尽管在过去十年中CLL的治疗取得了令人印象深刻的治疗进展，通常对已知疗法有抗性仍然是一个问题。了解耐药性并开发新的将CLL转变为可治愈的疾病的治疗策略是必要的。除了少数几个明显的例外，对化疗的反应通常通过细胞凋亡（一种程序性细胞死亡形式）发生。我们的目标是以鉴定使CLL细胞对凋亡敏感的药物，并鉴定可以防止复发。虽然常规细胞毒性的化学筛选是满足这一要求的有吸引力的策略，为了达到这一目标，这种方法受到无法可靠地培养CLL细胞超过48小时的阻碍。 vivo.这最终反映了我们在离体化学干扰CLL的能力方面的技术差距，测量功能和临床相关表型。在这里，我们将使用一种新的化学筛选方法，一种称为动态BH 3分析（DBP）的方法，该方法能够对化学物质进行功能测量。诱导凋亡变化，并且仅需要6-24小时的离体培养，从而最大化分子保真度和肿瘤细胞活力。使用超过2000种药物，我们不仅可以识别新的分子，敏感CLL细胞凋亡，但我们也将确定化学凋亡对于个体患者，在复发时失去或获得的敏感性。只对特定的药物敏感复发的肿瘤为联合化疗提供了令人兴奋的机会。终于明白了在治疗前和治疗后样品中的凋亡脆弱性的机制，我们将我们的用项目1和2中的大分子数据集测量功能性凋亡反应，至少104例CLL患者。总之，在CLL中成功鉴定凋亡增敏药物，这只能推进我们对CLL的分子理解，但可能导致真正新颖的治疗选择。