(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: 8686241
• 负责人: Aleksandar None Sekulic
• 金额: $ 38.2万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686241
• 关键词: Address; Advanced Malignant Neoplasm; Affect; Animal Model; Archives; BRAF gene; Biological Models; Cell Nucleus; Cell physiology; Cells; Clinic; Clinical; Coupled; Data; Development; Dose; Dreams; Drug Combinations; Drug resistance; Drug-sensitive; Event; Evolution; Flow Cytometry; Genome; Genomics; Goals; Grant; Heterogeneity; Housing; Human; Individual; Knowledge; Malignant Neoplasms; Metastatic Melanoma; Methods; Mining; Modeling; Molecular; Mus; Oncogenic; Outcome; Paraffin Embedding; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; Ploidies; Population; Process; Recovery; Relapse; Research; Research Infrastructure; 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; clinically relevant; cost; in vivo; inhibitor/antagonist; innovation; melanoma; mouse model; next generation sequencing; novel; oncology; pressure; public health relevance; research study; response; therapeutic development; therapy resistant; tumor; tumor growth; tumor progression

PROJECT SUMMARY 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 animal 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.

项目总结