Jennifer R. Grandis
Otolaryngology - Head and Neck Surgery, School of Medicine, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center
Over the past 25 years, my research has focused on signal transduction in head and neck squamous cell carcinoma (HNSCC) development and progression with the ultimate goal of targeting key pathways for therapeutic benefit. Our work has been characterized by bidirectional translation, taking key findings from the clinic and investigating mechanisms in a series of preclinical models, as well as developing novel therapeutic approaches in the laboratory and carrying out innovative clinical trials that employ these treatment strategies. More recently, we have harnessed the power of genetic analyses to elucidate the genetic and epigenetic underpinnings of HNSCC with the goal of developing predictive biomarkers for molecular therapies. This work forms the basis of my NCI OIA award (funded through 2025).
To begin to determine predictive biomarkers in HNSCC, we have carried out several neoadjuvant, window-of-opportunity clinical trials where HNSCC patients scheduled for surgical resection of their cancer are biopsied, then randomized to molecular targeting agent(s) or placebo for 2-3 weeks prior to surgery. The pre- and post-treatment tumor biopsies are then analyzed in conjunction with surrogate markers of clinical activity including Ki67 labeling in the tumor and anatomic imaging (e. g. CT scans). These studies have identified "exceptional responders" with genetic underpinnings that predict clinical responses, thus allowing us to realize the promise of precision medicine. In addition, taking advantage of the growing amount of genomic information available for human HNSCC tumors, we have designed clinical trials to test the effects of agents targeting oncogenic signaling pathways identified in these tumors. In addition, we have developed a large collection of patient derived xenografts (PDXs) that more closely reflect human cancers for preclinical modeling with the ultimate goal of developing "co-clinical trials".
The epidermal growth factor receptor (EGFR) is upregulated in many cancers, including HNSCC, and our research has contributed significantly to this field. The importance of EGFR in HNSCC is illustrated by the FDA approval of the EGFR monoclonal antibody cetuximab for the treatment of HNSCC in 2006. This is the first drug approved for this cancer in over 40 years. Despite ubiquitous EGFR expression in HNSCC tumors, cetuximab is effective in only a small subset of patients. We determine that targeting EGFR by downregulating RNA and protein expression using an antisense gene therapy approach was more effective in HNSCC preclinical models, patented this approach, obtained an investigator-initiated IND, obtained a patent, and have now completed phase I and phase II trials that demonstrated safety and efficacy of this approach alone and in combination with cetuximab. This agent was licensed to a biotech company for further clinical development. Ongoing studies are studying cetuximab resistance mechanisms, including activation of alternative signaling pathways in the setting of EGFR blockade.
We have identified oncogenic mutations of PIK3CA as predictive biomarkers to therapy such as PI3K pathway inhibitors and HER3 antagonists. The clinical relevance of our work is highlighted by our observation that patients with activating alterations of this pathway who happen to be taking non-steroidal anti-inflammatory drugs (NSAIDs) for other reasons had significantly improved survival. We are now planning to test the impact of aspirin on disease-specific recurrence and survival in multi-institutional prospective trial.
Signal Transducer and Activator of Transcripton-3 (STAT3) is an oncogenic transcription factor that is activated in most cancers including HNSCC. Our laboratory has been at the forefront of studying STAT signaling in HNSCC where STAT3 activation represents a potential resistance pathway for cetuximab therapy. In the absence of a clinical reagent that targets STAT3, we have developed a transcription factor decoy approach to block STAT3 activation. We demonstrated that this decoy is incorporated into HNSCC cells where it blocks STAT3 DNA binding, inhibits cell growth and decreases STAT3 target gene expression. Further investigation demonstrated antitumor efficacy in vivo and we obtained an investigator-initiated IND and completed a phase 0 trial in HNSCC patients. We subsequently modified our STAT3 decoy to create a more stable formulation. This cyclic STAT3 decoy was patented, we found no evidence of toxicity in preclinical murine models, and we are completing the IND-directed pharmacokinetic and toxicology studies to enable clinical testing. Our patents were recently licensed to a start-up company to accelerate clinical development.
List of Published Work in Google Scholar