Mechanistic, prognostic, and therapeutic impact of the mitochondrial fission GTPase DRP1 in melanoma

线粒体裂变 GTPase DRP1 对黑色素瘤的机制、预后和治疗影响

• 批准号: 9750085
• 负责人: Madhavika Niroshini Serasinghe
• 金额: $ 19.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750085
• 关键词: Address; Antibodies; Basic Science; Binding; Biochemical; Biochemistry; Biological Assay; Biological Markers; Biology; Cell Death; Cells; Cellular biology; Clinical; Collaborations; Crystallization; Data; Development; Disease; Disease Management; Disease Resistance; Docking; Early Diagnosis; Early treatment; Embryo; Exposure to; Faculty; Fibroblasts; Funding; Future; Goals; Guanosine Triphosphate Phosphohydrolases; Human; In Vitro; Institutes; Interdisciplinary Study; Investigational Therapies; K22 Award; Laboratories; Lead; Libraries; MAP Kinase Gene; MAPK3 gene; Maintenance; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Melanoma Cell; Mentorship; Methodology; Methods; Mission; Mitochondria; Modality; Modeling; Molecular Biology; Monitor; Monoclonal Antibodies; Mus; Mutation; Nevus; Oncogenes; Oncogenic; PTEN gene; Pathology; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Phosphorylation; Physiological Processes; Play; Postdoctoral Fellow; Prevention; Process; Proteins; Proto-Oncogene Proteins B-raf; Receptor Protein-Tyrosine Kinases; Research; Research Institute; Research Support; Resistance; Risk; Role; Science; Serine; Skin Cancer; Structure; Technical Expertise; Testing; Therapeutic; Therapeutic antibodies; Translating; Translational Research; Translations; United States National Institutes of Health; anticancer research; assay development; base; bench to bedside; cancer cell; career; career development; clinically relevant; drug development; drug discovery; experience; inhibitor/antagonist; innovation; insight; instructor; knock-down; medical schools; melanocyte; melanoma; member; mutant; novel; novel drug class; novel marker; novel therapeutics; patient subsets; personalized care; predictive marker; prevent; prognostic; prognostic assays; programs; senescence; skills; skin lesion; small molecule inhibitor; tenure track; therapeutic evaluation; tool; training opportunity; tumor metabolism; virtual

PROJECT SUMMARY Dr. Madhavika N. Serasinghe is an Instructor in the Department of Oncological Sciences at the Icahn School of Medicine at Mount Sinai (ISMMS). She has a strong background in biochemistry, molecular and cell biology, and extensive research experience in mitochondrial biology. During her post-doctoral studies and as an Instructor she studied the role of mitochondrial biology in oncogenic RAS-MAPK mediated transformation, with special focus on melanoma. The RAS- MAPK pathway is frequently hyper-activated in cancer through mutations in the receptor tyrosine kinases, RAS GTPase (e.g. RASG12V), or the BRAF kinase (e.g. BRAFV600E). The mitochondrial fission protein DRP1 is requisite for RASG12V mediated transformation of mouse embryonic fibroblasts, and phosphorylated DRP1 (DRP1S616℗) serves as a predictive biomarker for BRAFV600E positive melanoma progression. In the proposed project Dr. Serasinghe hypothesizes that DRP1 is required for melanocyte transformation by BRAFV600E, and that mitochondrial fission mediated by DRP1 plays an important role in overcoming oncogene induced senescence and progression of nevi to melanoma. In aim 1, she will examine the mechanistic impact of DRP1 mediated changes to mitochondrial biology on malignant transformation using a lentiviral BRAFV600E expression /PTEN knockdown model of primary human melanocytes. Her second aim will focus on translating her findings to a clinically relevant context. In collaboration with the Center for Therapeutic Antibody Development at ISMMS, she will develop a human specific monoclonal antibody as a basis for a prognostic assay to determine subsets of patients who require regular clinical monitoring for early detection and management of melanoma. As a part of aim 2, she will develop DRP1 specific small molecule inhibitors with potential therapeutic value in melanoma and other cancers. In collaboration with the Experimental Therapeutics Institute at ISMMS, utilizing structure-guided approaches to virtually screen a library of >20 million compounds, she will select and validate potential binders using in vitro and cell-based DRP1 activity and binding assays. These translational aims will provide Dr. Serasinghe hands-on experience in the drug discovery process as well as biomarker assay development, and allow her to acquire new skill sets and technical expertise for future translational research. The projected clinical aspects of these studies will enable her to gain further exposure to bench-to-bedside translation of basic research. Dr. Serasinghe’s immediate career goal is to develop an independent research program under the mentorship of Dr. Jerry Chipuk, obtain federal funding, and establish a laboratory at an academic cancer research institute as a tenure track faculty member to conduct high quality cancer research. At ISMMS, she will receive excellent mentorship, exceptional scientific and career development training, and opportunities to develop multidisciplinary collaborations to advance the scope of her research. Dr. Serasinghe’s long term career goal is to become a leader in melanoma research, and dedicate her efforts to discovering innovative preventative, prognostic, and therapeutic modalities against melanoma. The NCI-K22 award will provide Dr. Serasinghe valuable support to achieve her research and career goals, make important contributions to cancer research, and support the mission of the NIH and NCI.

项目概要 Madhavika N. Serasinghe 博士是伊坎医学院肿瘤科学系讲师 西奈山 (ISMMS)。她在生物化学、分子和细胞生物学方面拥有深厚的背景，并具有广泛的研究背景。 线粒体生物学研究经验。在她的博士后研究和作为讲师期间，她研究了 致癌 RAS-MAPK 介导转化中的线粒体生物学，特别关注黑色素瘤。 RAS- MAPK 通路在癌症中经常通过受体酪氨酸激酶 RAS GTPase 的突变而过度激活 （例如 RASG12V）或 BRAF 激酶（例如 BRAFV600E）。线粒体裂变蛋白 DRP1 是 RASG12V 所必需的 介导的小鼠胚胎成纤维细胞转化，磷酸化 DRP1 (DRP1S616℗) 可作为预测 BRAFV600E 阳性黑色素瘤进展的生物标志物。在拟议的项目中，Serasinghe 博士假设 DRP1 是 BRAFV600E 黑素细胞转化所必需的，并且 DRP1 介导的线粒体裂变起着重要作用 在克服癌基因诱导的衰老和痣向黑色素瘤的进展中发挥重要作用。在目标 1 中，她将 使用以下方法检查 DRP1 介导的线粒体生物学变化对恶性转化的机械影响 原代人黑素细胞的慢病毒 BRAFV600E 表达/PTEN 敲低模型。她的第二个目标将集中在 将她的发现转化为临床相关背景。与治疗性抗体中心合作 在 ISMMS 的开发中，她将开发一种人类特异性单克隆抗体，作为预后测定的基础 确定需要定期临床监测以早期发现和治疗黑色素瘤的患者亚群。 作为目标 2 的一部分，她将开发对黑色素瘤具有潜在治疗价值的 DRP1 特异性小分子抑制剂 和其他癌症。与 ISMMS 实验治疗研究所合作，利用结构引导 方法来虚拟筛选超过 2000 万种化合物的库，她将选择并验证潜在的结合剂 体外和基于细胞的 DRP1 活性和结合测定。这些转化目标将为 Serasinghe 博士提供实践机会 药物发现过程以及生物标志物检测开发方面的经验，使她能够获得新的技能 以及未来转化研究的技术专长。这些研究的预计临床方面将使她能够 进一步接触基础研究从实验室到临床的转化。 Serasinghe 博士的近期职业目标是 在 Jerry Chipuk 博士的指导下制定独立研究计划，获得联邦资助，并建立 作为终身教授在学术癌症研究所的实验室进行高质量的癌症研究 研究。在 ISMMS，她将获得出色的指导、卓越的科学和职业发展培训，以及 发展多学科合作以扩大她的研究范围的机会。 Serasinghe 博士的长期 职业目标是成为黑色素瘤研究的领导者，并致力于发现创新的预防、 黑色素瘤的预后和治疗方式。 NCI-K22 奖项将为 Serasinghe 博士提供宝贵的帮助 支持实现她的研究和职业目标，为癌症研究做出重要贡献，并支持使命 NIH 和 NCI 的。