Dissecting clonal diversity in melanoma to overcome therapy resistance andmetastasis

剖析黑色素瘤的克隆多样性以克服治疗耐药性和转移

基本信息

批准号：
10594536
负责人：
Vito William Rebecca
金额：
$ 11.9万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2020-04-06 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594536
关键词：
Ablation Address Advanced Malignant Neoplasm Advisory Committees BRAF gene Bar Codes Bioinformatics Biological Brain Budgets CRISPR/Cas technology Cells Clinical Combined Modality Therapy Competence Conflict of Interest Data Development Educational workshop Ensure FDA approved Faculty Funding Funding Agency Future Genetic Genomics Goals Grant Immunotherapy In Vitro Intrinsic drive Knock-out Knowledge Laboratories Liver Luciferases Lung Lysophosphatidic Acid Receptors MEKs Manuscripts Mediating Melanoma Cell Mentored Research Scientist Development Award Mentors Metastatic Melanoma Micrometastasis Modeling Molecular Neoplasm Metastasis Neural Crest Neuronal Plasticity Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Positioning Attribute Preparation Productivity Proliferating Property Proteins Proteomics RNA RNA interference screen Relapse Research Resistance Role Secure Subgroup Systems Biology Techniques Testing Therapeutic Therapy trial Time Training Translating Tumor Tissue Tumor Volume Validation Work Writing career career development clinical development clinically relevant genetic signature in vivo inhibitor inhibitor therapy insight melanoma mortality multidisciplinary mutant neoplastic cell novel therapeutic intervention patient derived xenograft model preclinical study programs response responsible research conduct self-renewal single cell analysis standard of care stem stem cells stem-like cell targeted treatment therapy resistant transcriptome sequencing tumor tumor ablation

项目摘要

Project Summary/Abstract Metastatic melanoma is challenging to clinically address. Although standard of care combination BRAF and MEK inhibitor (BRAFi/MEKi) therapy has high response rates in patients with BRAF-mutant melanoma, therapy relapse occurs in most cases. Work from our laboratory and others in the field has identified subpopulations of intrinsically BRAFi/MEKi-resistant melanoma cells that are highly metastatic and drivers of therapy relapse. These “persistent” melanoma cells display molecular and biologic properties akin to neural crest stem cells (NCSC), including high invasiveness, plasticity and self-renewal capacity. Our long-term goal is to elucidate the dominant molecular mechanisms that mediate the plasticity and aggressiveness of NCSC-like melanoma cells. Our preliminary studies identify a developmental LPAR1-YAP1 axis as critical for melanoma aggressiveness. One of the main objectives of this project will assess whether LPAR1-YAP1 activity represents an actionable vulnerability to ablate the metastatic potential and intrinsic resistance of NCSC-like cells. The proposed aims will leverage a multidisciplinary systems-biology approach spanning inducible genetic-editing techniques, lineage analysis of NCSC-like melanoma cells through time, metastatic patient-derived xenograft (Met-PDX) melanoma models, scRNAseq, RNA FISH and advanced bioinformatics, with the goal of translating the gained knowledge into novel therapeutic strategies for patients with advanced cancer. Another main goal is to establish an independent research program conducting multidisciplinary and collaborative research. To ensure the completion of the proposed work, my committee and I have identified four core competencies I will strengthen with continuous training, as well as didactic courses on single cell analysis and bioinformatic approaches. I will also participate in career training through workshops covering grant writing, manuscript preparation and presentation, responsible conduct of research, conflicts of interest, lab/budget management and guidance from my mentors. With the protected time and stability provided by the K01 award, as well as the comprehensive training I will receive, I am confident that I will be able to establish an independent research program and successfully acquire R01 funding. My short-term career goals are to: 1. Secure an independent faculty position and expand my scientific network of colleagues. 2. Define clonal diversity and molecular vulnerabilities of NCSC-like melanoma cells. 3. Continue to develop my scientific capabilities through my mentor/advisory committee and attain R01 funding. My long-term career goals are to: 1. Develop ongoing projects, expand into new directions and preclinical studies based on new results obtained. 2. Successfully renew R01 funding and attain alternate sources of funding, continue career development. 3. Translate discoveries clinically, train future mentees, and maintain a productive research program.

项目概要/摘要尽管 BRAF 和 MEK 联合治疗的标准治疗转移性黑色素瘤在临床上仍具有挑战性。抑制剂（BRAFi/MEKi）疗法对 BRAF 突变黑色素瘤患者具有较高的缓解率我们的实验室和该领域其他机构的工作已经确定了大多数情况下会出现复发。本质上对 BRAFi/MEKi 耐药的黑色素瘤细胞具有高度转移性，是治疗复发的驱动因素。这些“持久性”黑色素瘤细胞表现出类似于神经嵴干细胞的分子和生物学特性（NCSC），包括高侵袭性、可塑性和自我更新能力。我们的长期目标是阐明。介导 NCSC 样黑色素瘤细胞可塑性和侵袭性的主要分子机制。我们的初步研究确定发育中的 LPAR1-YAP1 轴对于黑色素瘤的侵袭性至关重要。该项目的主要目标之一将评估 LPAR1-YAP1 活动是否代表可操作的所提出的目标将是消除 NCSC 样细胞的转移潜力和内在抵抗力。利用跨学科系统生物学方法，涵盖诱导基因编辑技术、谱系通过时间分析 NCSC 样黑色素瘤细胞、转移性患者来源的异种移植 (Met-PDX) 黑色素瘤模型、scRNAseq、RNA FISH 和先进的生物信息学，目标是转化所获得的知识为晚期癌症患者提供新的治疗策略。另一个主要目标是建立一个独立的研究计划，进行多学科和为了确保完成拟议的工作，我和我的委员会确定了四项合作研究。我将通过持续培训以及单细胞分析教学课程来加强核心能力我还将通过研讨会参加职业培训，包括资助写作、手稿准备和演示、负责任的研究行为、利益冲突、实验室/预算凭借 K01 奖项提供的受保护的时间和稳定性，以及我将接受的全面培训，我相信我将能够建立一个独立的研究计划并成功获得R01资助。我的短期职业目标是： 1. 获得独立的教职职位并扩大我的同事科学网络。 2. 定义 NCSC 样黑色素瘤细胞的克隆多样性和分子脆弱性。 3. 通过我的导师/顾问委员会继续发展我的科学能力并获得 R01 资助。我的长期职业目标是： 1. 开发正在进行的项目，根据获得的新结果扩展到新的方向和临床前研究。 2. 成功续签R01资金并获得替代资金来源，继续职业发展。 3. 将发现转化为临床，培训未来的学员，并维持富有成效的研究计划。