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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：
10335137
负责人：
Piro Lito
金额：
$ 41.08万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335137
关键词：
Alternative Splicing Architecture BRAF gene Bar Codes Biochemical Biological Models Cancer Patient Cells Clinical Clinical Trials Clonal Expansion Clone Cells Colorectal Cancer Combination Drug 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 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 base 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