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Studies on the effects of a novel intermittent therapy on intratumoral clonal architecture and resistance

新型间歇疗法对瘤内克隆结构和耐药性影响的研究

基本信息

批准号：
10583567
负责人：
Piro Lito
金额：
$ 40.26万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2019-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583567
关键词：
Alternative Splicing Architecture BRAF gene Bar Codes Biochemical Biological Models Cancer Patient Cells Clinical Clinical Trials Clonal Expansion Colorectal Cancer Combination Drug Therapy Combined Modality Therapy Coupled Cues Derivation procedure Disease Drug Combinations Drug resistance Epidermal Growth Factor Receptor Evolution Experimental Models Exposure to FDA approved Gene Amplification Growth Heterogeneity Intervention Investigation MAP2K1 gene MEKs Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of thyroid Maps Mediating Medicine Melanoma Cell Methodology Modeling Mutation NF1 gene Nature Optics PTEN gene Patients Pattern Pharmaceutical Preparations Pharmacotherapy Population Process Property Recovery Resistance Science Signal Transduction System Testing Tumor-Derived Work antitumor effect cancer cell effective therapy fitness genetic evolution improved inhibitor innovation insight melanoma mutant novel patient derived xenograft model population based precision medicine pressure prevent prospective single cell sequencing success targeted treatment treatment effect tumor tumor growth tumor heterogeneity tumor microenvironment

项目摘要

ABSTRACT While it is well established that tumors evolve as they adapt to environmental cues, exactly how this process occurs remains under investigation. Precision medicines impose a relatively uniform selective pressure on the tumor and have well-described mechanisms of action, which enable a unique opportunity to study the determinants of evolutionary selection. By utilizing such treatments in conjunction with newly established methodologies that enable single-cell sequencing and prospective tracking of subclonal populations, this proposal aims to provide insight into the principles that govern the selection of resistance-causing alterations. BRAF mutant tumors were selected as an experimental model system because these are found in approximately 7% of cancer patients, including those with malignant melanoma, thyroid, colorectal and lung cancers. While RAF and/or MEK inhibitors are clinically effective active against these tumors, resistance is inevitable and almost all patients die from their disease, indicating the need to identify improved therapies. In recent work, we have established a conceptual framework that explains the selection and propagation of resistance-causing alterations and identified an intermittent three-drug combination therapy, which has a potent antitumor effect in BRAF V600E mutant lung cancer and melanoma patient-derived xenograft models. Based on these advances, we now proposed to study the effect of this treatment on intratumoral clonal heterogeneity and the emergence of resistance. In aim 1 we will determine genetic alterations that confer resistance to the intermittent combination treatment and determine the effect of this therapy on the intratumoral heterogeneity. In aim 2 we will prospectively evaluate the effect of therapy on clonal selection. In aim 3 we will investigate the mechanisms that confer fitness to the subclones that are selected during therapy. The impact of this proposal centers on advancing our understanding of the dynamics that drive the selection of subpopulations harboring resistance-causing alterations and on the identification of novel and more effective treatments for patients with BRAF mutant tumors.

摘要虽然肿瘤在适应环境的过程中会发生进化，但这一过程究竟是如何发生的呢？事件仍在调查中。精准药物对患者施加了相对均匀的选择压力，肿瘤，并有良好的描述机制的行动，这使得一个独特的机会，研究进化选择的决定因素通过利用这些治疗方法，方法，使单细胞测序和前瞻性跟踪亚克隆群体，这该提案旨在深入了解导致耐药性的改变的选择原则。选择BRAF突变体肿瘤作为实验模型系统，因为这些肿瘤存在于大约7%的癌症患者，包括恶性黑色素瘤、甲状腺癌、结直肠癌和肺癌患者癌的虽然RAF和/或MEK抑制剂对这些肿瘤具有临床有效活性，但耐药性是不可避免的。几乎所有患者都死于这种疾病，这表明需要确定改进的治疗方法。在最近的工作，我们已经建立了一个概念框架，解释了选择和传播并确定了一种间歇性的三种药物联合治疗，在BRAF V600 E突变型肺癌和黑色素瘤患者来源的异种移植模型中具有强效抗肿瘤作用。基于这些进展，我们现在建议研究这种治疗对肿瘤内克隆性生长的影响。异质性和耐药性的出现。在目标1中，我们将确定遗传改变，对间歇性联合治疗的抗性，并确定该疗法对肿瘤内异质性在目标2中，我们将前瞻性地评估治疗对克隆选择的影响。在目标3中，研究在治疗过程中选择的亚克隆赋予适应性的机制。的影响这一建议的核心是推进我们对推动选择亚群窝藏耐药引起的变化，并确定新的和更有效的 BRAF突变肿瘤患者的治疗。