Mechanisms of cooperation between MAPK and PI3K signaling in melanoma

 描述(申请人提供)：意义。BRAF和NRAS的致癌基因突变是黑色素瘤中最常见的基因突变，导致ERK1/2丝裂原激活蛋白激酶(MAPK)途径的持续激活。磷脂酰肌醇3-激酶(PI3K)信号的遗传异常也经常是黑色素瘤发生和维持所必需的。因此，这项研究的首要目标是了解MAPK和PI3K信号通路之间合作的潜在分子和生化机制，这些信号通路对黑色素瘤的维持至关重要，并识别可能有助于黑色素瘤患者通路靶向治疗的潜在分子靶点。接近。我将利用尖端筛选技术，如lentiCRISPR-Cas9基因敲除文库和核糖体图谱，阐明黑色素瘤细胞的基因组、转录和翻译图景，并确定在MAPK和PI3K信号通路的协调控制下的主要下游效应因子。为了了解PIK3CA的突变激活在黑色素瘤信号网络中的作用，我将采用遗传和药物抑制策略以及移植瘤模型来测试MAPK和PI3K途径联合抑制的协同抗增殖作用，以及mTORC1作为MAPK和PI3K活性的关键整合因子在PIK3CA突变的黑色素瘤维持中的作用。冲击力。本文提出的研究将有助于更好地理解MAPK和PI3K通路在黑色素瘤信号转导中的机制基础，并直接影响其他类型的癌症，这些途径在分子和生化环境中也有类似的协同作用。环境我的主要导师马丁·麦克马洪博士是Efim Guzik癌症生物学特聘教授，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，为职业发展提供科学专业知识和指导。职业目标。我的综合研究培训计划包括将我的研究专长扩展到新的技术领域，在高影响力的期刊上发表我的研究成果，以及建立我自己的独立研究计划。此外，我还将参加加州大学旧金山分校的专业、职业和教学发展研讨会，以增强我获得学术教员职位和获得R-Level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.