(PQD1) Clonal heterogeneity and targeted therapy resistance in melanoma

(PQD1) 黑色素瘤的克隆异质性和靶向治疗耐药性

• 批准号: 9323828
• 负责人: Aleksandar None Sekulic
• 金额: $ 34.83万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-11 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323828
• 关键词: Address; Advanced Malignant Neoplasm; Affect; Animal Model; Archives; BRAF gene; Biological Models; Cell Nucleus; Cell physiology; Cells; Clinic; Clinical; Coupled; Data; Dose; Dreams; Drug Combinations; Drug resistance; Drug-sensitive; Event; Evolution; Flow Cytometry; Genome; Genomics; Goals; Grant; Heterogeneity; Human; Knowledge; Malignant Neoplasms; Metastatic Melanoma; Methods; Mining; Modeling; Modernization; Molecular; Mus; Oncogenic; Outcome; Paraffin Embedding; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; Ploidies; Population; Process; Recovery; Relapse; Research; Resistance; Resistance development; Resource Informatics; Resources; Role; Sampling; Series; Solid Neoplasm; Sorting - Cell Movement; Testing; Therapeutic; Time; Tissue Banks; Tissues; Xenograft Model; base; cancer cell; clinical development; clinically relevant; cost; experimental study; genomic data; in vivo; individual patient; informatics infrastructure; inhibitor/antagonist; innovation; melanoma; mouse model; next generation sequencing; novel; oncology; patient subsets; pressure; public health relevance; response; targeted agent; targeted treatment; therapeutic development; therapy resistant; tumor; tumor growth; tumor heterogeneity; tumor progression

DESCRIPTION (provided by applicant): PQD1: Clonal heterogeneity and targeted therapy resistance in melanoma. Molecular instability of cancer cells generates diversity that, in turn, enables tumor evolution. A strong selective pressure from targeted therapies can provide dramatic clinical responses but also drive such evolution to yield rapid drug resistant tumor growth. To effectively address this key challenge of modern day oncology, it is imperative to better understand the basic mechanisms underlying evolution of resistance in patients in vivo. We hypothesize that development of clinical resistance to targeted therapy in advanced cancers is a function of marked tumor heterogeneity and clonal selection rather than cellular adaptation to therapeutic pressure. Our proposal will test this hypothesis using targeted inhibition of oncogenic BRAF in melanoma as a model system. To achieve this we will employ a highly innovative approach that combines flow cytometry-based sorting of tumor nuclei directly from solid tumor archived paraffin-embedded clinical samples with next generation sequencing, providing a unique opportunity to exploit the extensive Mayo Clinic resources of archived clinically annotated melanoma tissues. Genomic sequence data obtained in these experiments from distinct clonal tumor populations sorted from a series of patient matched sensitive and resistant tissues will be used to define clonal tumor lineages and respective molecular events associated with resistance. We will also leverage the novel and robust informatics resources of our Stand Up To Cancer (SU2C) Melanoma Dream Team effort for clinically relevant interpretation of genomic data in this proposal. Finally, we will explore approaches to modulate development of resistance arising in patients in vivo in a unique, highly clinically relevant anima model system. Using tumorgrafts derived from patient's matched pre-treatment (sensitive) and relapsed (resistant) tissues, we will test the effects of altering drug dose and timing and explore rational combination treatments based on genomic data from paired tissues. The key issue addressed in this proposal holds relevance not only to melanoma but solid tumors in general. The outcomes of our proposed research have potential to significantly impact our understanding of drug resistance and the development of clinically relevant approaches to overcome it, which is of particular relevance as numerous targeted agents are reaching the clinic.

描述(申请人提供)：PQD1：黑色素瘤的克隆性异质性和靶向治疗耐药性。癌细胞的分子不稳定会产生多样性，进而使肿瘤进化成为可能。来自靶向治疗的强大选择压力可以提供戏剧性的临床反应，但也可以推动这种进化，以产生快速的耐药肿瘤生长。为了有效地应对现代肿瘤学的这一关键挑战，必须更好地了解患者体内耐药进化的基本机制。我们假设，晚期癌症患者对靶向治疗的临床耐药性的形成是肿瘤显着异质性和克隆选择的结果，而不是细胞对治疗压力的适应。我们的建议将使用靶向抑制黑色素瘤致癌BRAF作为模型系统来检验这一假说。为了实现这一目标，我们将采用一种高度创新的方法，将直接从实体瘤存档石蜡包埋临床样本中对肿瘤细胞核进行基于流式细胞术的分类与下一代测序相结合，提供一个独特的机会来开发存档的临床注释黑色素瘤组织的广泛的梅奥诊所资源。在这些实验中，从一系列患者匹配的敏感和耐药组织中分离的不同克隆性肿瘤群体中获得的基因组序列数据将用于确定克隆性肿瘤谱系和与耐药相关的相应分子事件。我们还将利用我们的抗癌(SU2C)黑色素瘤梦想团队努力的新颖和强大的信息学资源，对该提案中的基因组数据进行临床相关的解释。最后，我们将探索在一个独特的、与临床高度相关的动物模型系统中调节患者体内产生的耐药性发展的方法。使用来自患者匹配的治疗前(敏感)和复发(耐药)组织的肿瘤移植，我们将测试改变药物剂量和时机的效果，并探索 根据配对组织的基因组数据进行合理的组合治疗。这项提案中涉及的关键问题不仅与黑色素瘤有关，而且与实体肿瘤总体上有关。我们建议的研究结果有可能显著影响我们对耐药性的理解和克服它的临床相关方法的开发，这一点特别相关，因为许多靶向药物正在进入临床。