Repurposing systemic therapies to improve clinical outcomes in advanced basal cell cancer

改变系统治疗的目的以改善晚期基底细胞的临床结果 癌症 项目总结 这是为Kavita博士申请K23指导的以患者为导向的研究职业发展奖 斯坦福大学助理教授沙林说。萨林博士正在确立自己作为一名翻译研究员的地位 皮肤肿瘤学，专注于为非黑色素瘤患者开发合理设计的基于分子的疗法 皮肤癌。K23奖将通过以下方式为Sarin博士提供实现这一目标所需的支持：1)使她能够获得 通过研究培训高级生物信息学、转化研究、临床试验设计和皮肤肿瘤学； 指导和授课；2)在有经验的教师的指导下，提供有保障的时间来追求她的研究目标 多学科导师团队；以及3)使出版物和演讲机会在该领域获得认可 皮肤肿瘤学。Sarin博士组建了一支由翻译专家组成的导师和合作者团队 晚期基底细胞癌的实验室研究和临床试验(Anthony Oro M.D.Ph.D.，Jean Tang M.D.Ph.D.， Ervin Epstein医学博士，Anne Chang医学博士)和应用生物信息学(Howard Chang，医学博士，Marina Sirota 博士学位)。在她的指导团队的帮助下，Sarin博士制定了一项全面的职业发展计划，从 指导研究员到皮肤肿瘤学的独立翻译研究员。 萨林博士的研究计划旨在研究新的靶向和免疫检查点疗法，用于治疗 晚期基底细胞癌(BCC)。使用基于生物信息学的药物重新定位屏幕，她确定了组蛋白 脱乙酰酶抑制剂，伏立康，作为治疗晚期基底细胞癌的候选药物。随后的临床前研究表明 该涡旋器可以抑制BCC细胞系和肿瘤移植物中的Hedgehog信号和BCC生长。在目标1中，Dr。 沙林将机械地询问HDAC1在HH信号中的作用，并进行2期开放标记临床试验 24例晚期基底细胞癌患者的稳涡器治疗。在目标2中，萨林博士将研究基因组、转录组和免疫学。 与PD-1在晚期基底细胞癌中的阻断有关。萨林博士得到了她的导师和斯坦福大学的全力支持 大学，他们为该提案提供指导、样本和财政支持。成功完成这项工作 提案将允许萨林博士发展成为一名独立的首席研究员所需的多学科技能 基于分子的皮肤癌疗法的发展，并将为未来的R01产生初步数据 格兰特。

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.