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Defining the Role of Metabolic Heterogeneity in Melanoma Dissemination and Therapy Escape

定义代谢异质性在黑色素瘤传播和治疗逃避中的作用

基本信息

批准号：
10244001
负责人：
Inna Smalley
金额：
$ 24.9万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10244001
关键词：
Address Affect Appearance Award BRAF gene Behavior Bioinformatics Biology Biometry Blood Circulation Career Mobility Cell Culture Techniques Cell Line Cells Chronic Computational Biology Dependence Development Distant Metastasis Dose Drug Exposure Drug resistance Educational workshop Evolution Failure Gene Expression Gene Expression Profile Genotype Glycolysis Goals Grant Growth Heterogeneity Hypoxia Immunofluorescence Immunologic Impairment In Vitro Individual Knowledge MEKs Malignant Neoplasms Mass Spectrum Analysis Melanoma Cell Mentors Metabolic Metabolic Marker Metabolism Modeling Nature Neoplasm Metastasis Oxidative Phosphorylation Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Phenotype Population Research Research Personnel Resistance Role SLC2A1 gene Schedule Scientist Shapes Signal Transduction Site Specimen System Testing Therapeutic Time Treatment Efficacy Variant Work Xenograft Model Xenograft procedure base drug sensitivity fitness glucose uptake improved in vivo in vivo Model inhibitor/antagonist large scale data mRNA Expression mathematical model melanoma metabolic phenotype metabolomics mutant neoplastic cell predictive modeling programs protein expression resistance mechanism response single-cell RNA sequencing skills targeted agent targeted treatment treatment response tumor tumor heterogeneity

项目摘要

PROJECT SUMMARY/ ABSTRACT Despite promising initial responses, most BRAF-mutant melanoma patients eventually fail on BRAF inhibitor therapy. The task of understanding therapeutic escape and dissemination is complicated further by the countless number of resistance mechanisms identified so far and the realization that multiple cellular phenotypes may exists within a single genotype. The roles of intra-tumoral heterogeneity in progression and drug resistance are poorly understood, and we submit that strategies tackling this diversity are needed for durable therapeutic responses in patients. We hypothesize that: (i) drug-induced tumor cell phenotypic heterogeneity is driven by the development of inter-dependent and cooperative metabolic niches that promote tumor dissemination and affect the response to therapeutics; and (ii) therapeutic approaches that exploit intra- clonal metabolic competition will give more durable responses in melanoma patients. We will define the metabolic landscape of OXPHOS-dependent and glycolysis-dependent subpopulations in cell culture, xenografts, patient-derived xenografts (PDX) and patient specimens using single-cell RNAseq, global metabolomics and targeted expression panels. We will test how OXPHOS-dependent and glycolysis- dependent subpopulations cooperate to drive metastasis and define the drug sensitivities of the individual subpopulations in vitro and in xenografts and PDXs. We will test if disrupting either OXPHOS or glycolysis, pharmacologically or through gene expression targeting, shapes the metastatic potential or the emergence and heterogeneity of drug resistant subpopulations. We will devise a mathematical model to define optimal, evolutionary-informed dosing of BRAF/MEK plus metabolic inhibitor combinations that impair clonal cooperation and maximize duration of the therapeutic response. These models will be validated in vitro and in PDX models. The K99/R00 award would allow the candidate to conduct the proposed studies under the continued guidance of their primary mentor, Dr. John Cleveland, together with a panel of co-mentors who are renowned experts in melanoma biology, PDX modeling, cancer evolution, metabolism, and statistical and computational approaches to systems-wide large-scale data set analysis. During the K99 phase, the candidate will further develop their knowledge in melanoma metabolism and evolutionary biology, as well as their technical abilities in mass-spectrometry-based metabolomics, advanced computational biology, bioinformatics and biostatistics. With the help of their committee and various seminars, courses and workshops, the candidate will become a stronger scientist, manager, grant writer and mentor, all skills necessary to be an independent investigator. Overall, the proposed work will provide the rationale for therapeutic approaches that exploit intra-clonal metabolic competition to give more durable responses in melanoma patients, as well as a timely career transition for a candidate with strong potential to be a successful independent investigator.

项目摘要/摘要