The goal of our research program is to exploit the emerging information on dysregulated signaling circuitries and individual genomic and molecular alterations to identify new therapeutic options to prevent and treat cancer. Our 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 tumor progression and immune escape, aimed at identifying new cancer therapies. The four primary research areas in our laboratory include the study of: 1) G proteins and GPCR signaling in cell growth control and cancer; 2) head and neck cancer (HNSCC), focused on precision prevention and treatment; 3) immune oncology, with emphasis on the study of multimodal precision immunotherapies for HNSCC and other malignancies; and 4) the role of GPCRs in cancer immune evasion and as new immunotherapy targets.

Specifically, we have shown that human and virally-encoded G proteins and G protein coupled receptors (GPCRs) can display potent oncogenic activity, and that many human malignancies harbor mutations in this receptor family and their linked G proteins. We have studied the tumorigenic activity of G proteins and GPCRs to dissect the signaling circuities regulating normal and aberrant cell proliferation, cancer progression, immune evasion, tumor-induced angiogenesis, and metastasis. We are now investigating 1) the mechanisms by which genetic mutations in Gαq proteins (encoded by the GNAQ oncogene) initiate uveal and cutaneous melanoma, with emphasis on the regulation of the Hippo pathway; 2) the role of Gαs (encoded by the GNAS oncogene) and its target, PKA, in cancer; and 3) how mutations, overexpression, and oncocrine activation of GPCRs contribute to tumor progression, escape from immune surveillance, and therapy resistance to targeted agents and immunotherapies.

In parallel, 4) we are exploring the role of the PI3K/mTOR and Hippo signaling circuitry in cancers of the oral cavity, a disease that results in 300,000 deaths each year worldwide. Based on our prior studies, and emerging results from our recently completed multi-institutional clinical trial targeting mTOR in oral cancer, we are now investigating the effectiveness and mechanism of action of direct and indirect PI3K/mTOR inhibitors for oral cancer prevention and treatment, as single agents and as part of novel multimodal immunotherapy approaches. We are also exploring new treatment options targeting central signaling nodes in the Hippo pathway, as well as exploiting our new syngeneic mouse models of oral cancer to identify systems vulnerabilities that can be targeted therapeutically to enhance the clinical response to immune checkpoint blockade.