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.
Melanoma is the deadliest form of skin cancer. Once it metastasizes, melanoma is often considered one of the most aggressive and therapeutic resistant cancers. The main objective of this research is to understand how the melanoma cell communicates through the cooperation of various signaling pathways to promote proliferation, growth and survival. The successful completion of this research project will identify novel targets within these signaling networks that can be used to generate pathway-targeted therapy and improve the treatment of melanoma patients.
| Silva, Jillian M; Deuker, Marian M; Baguley, Bruce C et al. (2017) PIK3CA-mutated melanoma cells rely on cooperative signaling through mTORC1/2 for sustained proliferation. Pigment Cell Melanoma Res 30:353-367 |
