Overcoming resistance to targeted therapy in cancer

克服癌症靶向治疗的耐药性

• 批准号: 9247961
• 负责人: Levi A. Garraway
• 金额: $ 8.7万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-24 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247961
• 关键词: Advanced Malignant Neoplasm; Aftercare; Antineoplastic Agents; BRAF gene; Biopsy; Bypass; Categories; Cells; Chromatin; Clinical; Dependency; Disseminated Malignant Neoplasm; Drug Combinations; Drug resistance; Evolution; Glean; Goals; Health; Individual; MAP Kinase Gene; Malignant Neoplasms; Medical; Mitogen-Activated Protein Kinases; Modality; Nature; Oncogenes; Oncogenic; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Refractory; Regimen; Regulation; Research; Resistance; Resistance development; Sampling; Signal Transduction; Testing; Therapeutic; Tissues; Work; anti-cancer therapeutic; base; cancer type; design; insight; kinase inhibitor; melanoma; mutant; neoplastic cell; novel therapeutics; programs; resistance mechanism; targeted treatment; tumor; tumor progression

 DESCRIPTION (provided by applicant): Overcoming resistance to targeted therapy in cancer Project Summary The challenge of drug resistance represents a pervasive barrier that confounds the ultimate goal of cure or long-term control of metastatic cancer. Intensive studies of resistance to targeted therapies by our group in recent years have revealed three over-arching challenges. First, resistance is multifactorial: many individual resistance mechanisms thwart the efficacy of various targeted anticancer therapeutic regimens, and there is no evidence that their discovery has saturated. Second, resistance is heterogeneous: multiple different resistance mechanisms often arise in a given patient-even within a single tumor lesion1. Third, resistance is vastly under-sampled in the clinical arena: few paired pre-treatment and post-resistance biopsies are obtained clinically, and such tissues are only seldom subjected to systematic characterization2. The guiding hypothesis of this research is that the spectrum of resistance mechanisms for any given cancer therapeutic modality might coalesce onto a much smaller set of critical downstream effector "nodes". Discerning the mechanisms operant within such "points of coalescence" should yield new insights into oncogenic dependencies and illuminate guiding principles for the design of novel therapeutic combinations. In recent years, we have evaluated this "coalescence hypothesis" by systematically characterizing mechanisms of resistance to MAP kinase pathway inhibition in BRAF-mutant melanoma and other oncogene- driven cancers. Indeed, many individual MAP kinase resistance mechanisms may coalesce at the level of transcriptional (or chromatin) regulation. This convergence re-engages core MAPK transcriptional program(s) or alternative (ERK-independent) transcriptional programs arising from bypass signaling or germane to "pathway-indifferent" cell states. Accordingly, one objective of this work is to define the convergent downstream outputs elaborated by MAP kinase inhibitor resistance mechanisms, and the factors that govern them. In parallel, we will characterize the coalescence of resistance mechanisms to targeted therapeutics in other cancers. Finally, we will describe drug-resistant and "drug-indifferent" cell states in treatment-refractory tumors. Detailed characterization of resistance categories and the mechanistic coalescence implied therein may reveal fundamental new insights into the nature of cancer dependencies and their evolution during tumor progression and treatment. Insights gleaned from this research may aid the design of higher-order therapeutic combinations that attack multiple tumor dependencies and resistance nodes. This framework for studying the mechanistic coalescence that underpins drug resistance is applicable to many cancer types. Therefore, these efforts could offer guiding principles that become generalizable across many tumor types and therapeutic modalities.

 描述（由申请人提供）：克服癌症靶向治疗的耐药性 项目摘要 耐药性的挑战是一个普遍存在的障碍，阻碍了转移性癌症的治愈或长期控制的最终目标。近年来，我们小组对靶向治疗耐药性的深入研究揭示了三个首要挑战。首先，耐药性是多因素的：许多个体耐药机制阻碍了各种靶向抗癌治疗方案的功效，并且没有证据表明它们的发现已经饱和。其次，耐药性是异质的：特定患者中经常会出现多种不同的耐药机制，甚至在单个肿瘤病变内也是如此。第三，临床领域对耐药性的采样严重不足：临床上很少获得配对的治疗前和耐药后活检，而且此类组织很少进行系统表征2。这项研究的指导性假设是，任何给定癌症治疗方式的耐药机制谱可能会合并到一组小得多的关键下游效应器“节点”上。辨别这种“融合点”的运作机制应该会对致癌依赖性产生新的见解，并阐明设计新型治疗组合的指导原则。近年来，我们通过系统地表征 BRAF 突变黑色素瘤和其他癌基因驱动的癌症对 MAP 激酶途径抑制的抵抗机制，评估了这种“合并假说”。事实上，许多单独的 MAP 激酶抵抗机制可能在转录（或染色质）调节水平上结合。这种融合重新参与核心 MAPK 转录程序或由旁路信号传导或与“通路无关”细胞状态密切相关的替代（ERK 独立）转录程序。因此，这项工作的一个目标是定义 MAP 激酶抑制剂耐药机制所阐述的收敛下游输出，以及控制它们的因素。与此同时，我们将描述其他癌症中靶向治疗的耐药机制的合并。最后，我们将描述难治性肿瘤中的耐药和“药物无关”细胞状态。详细的 耐药类别的表征和其中隐含的机制合并可能揭示对癌症依赖性的本质及其在肿瘤进展和治疗过程中的演变的基本新见解。从这项研究中收集的见解可能有助于设计攻击多种肿瘤依赖性和耐药节点的高阶治疗组合。这个用于研究支撑耐药性的机械合并的框架适用于许多癌症类型。因此，这些努力可以提供可推广到许多肿瘤类型和治疗方式的指导原则。

项目成果

Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer.

• DOI: 10.1158/2159-8290.cd-16-0305
• 发表时间: 2016-10
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Le X;Antony R;Razavi P;Treacy DJ;Luo F;Ghandi M;Castel P;Scaltriti M;Baselga J;Garraway LA
• 通讯作者: Garraway LA