REPURPOSING SYSTEMIC THERAPIES TO IMPROVE CLINICAL OUTCOMES IN ADVANCED BASAL CELL CANCER PROJECT SUMMARY This is an application for a K23 Mentored Patient-Oriented Research Career Development Award for Dr. Kavita Sarin, an Assistant Professor at Stanford University. Dr. Sarin is establishing herself as a translational investigator in cutaneous oncology, focused on developing rationally-designed molecular-based therapies for patients with non-melanoma skin cancer. The K23 Award will provide Dr. Sarin the support needed to achieve this goal by: 1) enabling her to obtain training in advanced bioinformatics, translational research, clinical trial design, and cutaneous oncology through research, mentorship and didactics; 2) providing protected time to pursue her research goals under the guidance of an experienced multidisciplinary team of mentors; and 3) enabling publications and speaking opportunities to gain recognition in the field of cutaneous oncology. Dr. Sarin has assembled a team of mentors and collaborators with expertise in translational laboratory investigation and clinical trials in advanced basal cell cancer (Anthony Oro M.D. Ph.D., Jean Tang M.D. Ph.D., Ervin Epstein M.D. Ph.D., Anne Chang M.D. Ph.D.) and applied bioinformatics (Howard Chang M.D. Ph.D., Marina Sirota Ph.D.). With her mentorship team, Dr. Sarin has developed a comprehensive career development plan to transition from a mentored investigator to an independent translational investigator in cutaneous oncology. Dr. Sarin?s research plan aims to investigate new targeted and immune-checkpoint therapies for the treatment of advanced basal cell cancer (BCC). Using a bioinformatics-based drug-repositioning screen, she identified the histone deacetylase inhibitor, vorinostat, as a candidate therapeutic for advanced BCC. Subsequent preclinical studies demonstrated that vorinostat can suppress hedgehog signaling and BCC growth in BCC cell lines and tumor allografts.
In Aim 1, Dr. Sarin will mechanistically interrogate the role of HDAC1 in Hh signaling and conduct a Phase 2 open-label clinical trial of vorinostat in 24 patients with advanced BCC.
In Aim 2, Dr. Sarin will investigate genomic, transcriptomic, and immunologic correlates to PD-1 blockade in advanced basal cell cancer. Dr. Sarin has the full support of her mentors and Stanford University, who are providing guidance, samples, and financial support for the proposal. Successful completion of this proposal will allow Dr. Sarin to develop the multidisciplinary skills needed to be an independent principal investigator in the development of molecular-based therapeutics for skin cancer and will generate the preliminary data for a future R01 grant.
REPURPOSING SYSTEMIC THERAPIES TO IMPROVE CLINICAL OUTCOMES IN ADVANCED BASAL CELL CANCER PROJECT NARRATIVE Basal cell cancers (BCCs) are the most common cancer in the United States with over 2 million cases diagnosed annually. Advanced BCCs are highly aggressive with a poor prognosis, high resistance to Smoothened inhibitors, and limited alternative therapeutic options. This ?data to bench to bedside? proposal aims to investigate new targeted and immune- checkpoint therapies for the treatment of advanced basal cell cancer (BCC). Specifically, Dr. Sarin will investigate the histone deacetylase inhibitor, vorinostat, with in vitro mechanistic studies and a Phase 2 clinical trial for advanced BCC. In a second independent aim, she will explore genomic, transcriptomic, and immunologic correlates with response to the PD- 1 inhibitor, pembrolizumab, in advanced BCC.
