Mechanisms of cooperation between MAPK and PI3K signaling in melanoma

 描述（由申请人提供）：意义。BRAF和NRAS的致癌突变是黑色素瘤中最常见的遗传改变之一，导致ERK 1/2丝裂原活化蛋白激酶（MAPK）通路持续活化。磷脂酰肌醇3-激酶（PI 3 K）信号传导中的遗传畸变也通常是黑色素瘤进展和维持所需的。因此，本研究的总体目标是了解MAPK和PI 3 K信号通路之间合作的潜在分子和生化机制，这些机制对黑色素瘤的维持至关重要，并确定可能有助于黑色素瘤患者的通路靶向治疗发展的潜在分子靶点。Approach.我将利用尖端的筛选技术，如lentiCRISPR-Cas9敲除文库和核糖体分析，阐明黑色素瘤细胞的基因组，转录和翻译景观，并确定在MAPK和PI 3 K信号通路的协调控制下的主要下游效应子。为了了解PIK 3CA突变激活对黑色素瘤信号传导网络的贡献，我将采用遗传和药理学抑制策略和异种移植肿瘤模型来测试MAPK和PI 3 K通路联合抑制的协同抗增殖作用，以及mTORC 1作为MAPK和PI 3 K活性的关键整合剂对PIK 3CA突变黑色素瘤维持的作用。冲击本文提出的研究将阐明MAPK和PI 3 K通路合作参与黑色素瘤信号传导的机制基础，并直接影响其他类型的癌症，这些癌症具有相似的分子和生物化学景观，这些通路也合作。环境我的主要导师Martin McMahon博士是Efim Guzik癌症生物学杰出教授，也是黑色素瘤研究的杰出领导者。此外，Patricia Calarco博士和Davide Ruggero博士将在我的咨询委员会任职，就职业发展提供科学专门知识和指导。职业目标。我的综合研究培训计划包括将我的研究专业知识扩展到新的技术领域，在高影响力期刊上发表我的研究，并建立自己的独立研究计划。此外，我还将参加UCSF的专业，职业和教学发展研讨会，以加强我获得学术教师职位和获得R级资金的竞争力。此外，完成这些研究和职业发展培训活动将有助于我成为一名非常成功的独立调查员。

 DESCRIPTION (provided by applicant): Significance. Oncogenic mutations in BRAF and NRAS are among the most common genetic alterations that occur in melanoma leading to the sustained activation of the ERK1/2 mitogen-activated protein kinase (MAPK) pathway. Genetic aberrations in phosphoinositide 3-kinase (PI3K) signaling are also often required for melanoma progression and maintenance. Thus, the overarching goal of this research is to understand the underlying molecular and biochemical mechanisms of cooperation between the MAPK and PI3K signaling pathways that are essential for melanoma maintenance and to identify potential molecular targets that could contribute to the development of pathway-targeted therapy for melanoma patients. Approach. I will utilize cutting-edge screening technologies, such as a lentiCRISPR-Cas9 knockout library and ribosome profiling, to elucidate the genomic, transcriptional, and translational landscape of the melanoma cell and identify the major downstream effectors that are under the coordinate control of both the MAPK and PI3K signaling pathways. To understand the contribution of mutational activation of PIK3CA to the melanoma signaling networks, I will employ genetic and pharmacological inhibitory strategies and xenograft tumor models to test the synergistic antiproliferative effects of combined MAPK and PI3K pathway inhibition and the role of mTORC1 as a key integrator of MAPK and PI3K activity for PIK3CA mutant melanoma maintenance . Impact. The research proposed here will illuminate a greater comprehension of the mechanistic foundation of MAPK and PI3K pathway cooperation involved in melanoma signaling with direct implications in other types of cancer that share a similar molecular and biochemical landscape in which these pathway also cooperate. Environment. My primary mentor, Dr. Martin McMahon, is an Efim Guzik Distinguished Professor of Cancer Biology and a prominent leader in melanoma research. Moreover, Drs. Patricia Calarco and Davide Ruggero will be serving on my Advisory Committee to provide scientific expertise and guidance on career development. Career Goals. My comprehensive research training program includes expanding my research expertise into new technological areas, publishing my research in high-impact journals and establishing my own independent research program. In addition, I will also participate in the professional, career and teaching development workshops at UCSF to strengthen my competitiveness for attaining an academic faculty position and securing R-level funding. Furthermore, completion of these research and career development training activities will facilitate my progression into a highly successful independent investigator.