I am a basic scientist with a passion for exploiting the emerging information on dysregulated signaling circuitries and individual genomic and molecular alterations to develop new precision therapies to prevent and treat cancer. My laboratory has focused on the study of growth-promoting signal transduction pathways, the nature of the dysregulated signaling networks in cancer, and on the use of genomic, proteomic, and system biology approaches to study cancer initiation and progression. Specifically, we have shown that human and virally-encoded G proteins and G protein coupled receptors (GPCRs) can display potent oncogenic activity. Emerging evidence from our laboratory has revealed that malignant cells often hijack the normal physiological functions of GPCRs to proliferate autonomously, evade immune detection, enhance their nutrient and oxygen supply, invade their surrounding tissues, and disseminate to other organs. Strikingly, our recent analysis of human cancer genomes revealed an unanticipated high frequency of mutations in G proteins and GPCRs in most tumor types. Indeed, nearly 30% of all human cancers harbor mutations in GPCRs or G proteins. We are now investigating the mechanisms by which genetic mutations in Gαq proteins initiate uveal and
J. SILVIO GUTKIND
cutaneous melanoma, the role of Gαs and its target, PKA, in cancer, with emphasis on colorectal cancer, and how mutations and autocrine activation of GPCRs contribute to tumor progression, immune evasion, and therapy resistance.In parallel, we are exploring the role of the mTOR pathway in head and neck cancer, a disease that results in 250,000 deaths each year worldwide. Based on our studies, and emerging results from our multi-institutional clinical trial targeting mTOR in oral cancer, we are now investigating the effectiveness and mechanism of action of PI3K/mTOR inhibitors for oral cancer prevention and treatment, as single agents and as part of novel signal transduction-based co-targeting strategies. I have led a national and international effort addressing oral and head and neck malignancies as the Chief of the Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, and as a leader of a NCI/trans-NIH program in oral cancer research, from 1998 until the recent relocation of our research team to the University of California San Diego (UCSD) Department of Pharmacology and Moores Cancer Center in September, 2015. I am currently the Associate Director of Basic Science, and Co-Director of the Head and Neck Cancer Center at the Moores Cancer Center at UCSD. Over the years, I have been fortunate to have the opportunity to work with a superb team of talented students, post-doctoral fellows, and outstanding collaborators, who share our passion for translating our findings (discoveries) into new, effective, safe, and low cost precision cancer therapeutic options to prevent and treat human malignancies.
G proteins/GPCRs and cancer
GPCRs, the largest family of cell-surface molecules involved in signal transmission, have recently emerged as crucial players in tumour growth and metastasis.
The PI3K/mTOR signaling pathway is one of the most frequently dysregulated
molecular mechanisms in HNSCC. mTOR inhibition halts tumor progression.
Recent revolutionary therapeutic strategies restoring T cell mediated anti-tumor immunity by immune modulating agents have achieved remarkable clinical responses including in HNSCC.
Around 90% of ocular melanomas harbor gain-of- function mutations in GNAQ or GNA11, where they are now considered to represent the driver oncogenes.