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

改善晚期基底细胞癌临床结局的药物治疗 癌 项目摘要 这是K23指导的以患者为导向的研究职业发展奖的申请。 斯坦福大学的助理教授萨林说。萨林博士正在建立自己作为一个翻译研究员， 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 通过研究进行高级生物信息学、转化研究、临床试验设计和皮肤肿瘤学方面的培训， 导师和教学法; 2）提供受保护的时间，在经验丰富的指导下追求她的研究目标 多学科导师团队; 3）使出版物和演讲机会在该领域获得认可 皮肤肿瘤学Sarin博士组建了一个由导师和合作者组成的团队， 在晚期基底细胞癌中的实验室研究和临床试验（Anthony Oro M.D.博士，Jean Tang医学博士哲学博士、 Ervin Epstein医学博士哲学博士、Anne Chang医学博士博士）和应用生物信息学（霍华德张M. D.哲学博士、玛丽娜·西罗塔 Ph.D.）。Sarin博士与她的导师团队一起制定了一个全面的职业发展计划， 指导研究者成为皮肤肿瘤学的独立翻译研究者。 Sarin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）。利用基于生物信息学的药物重新定位筛选， 脱乙酰酶抑制剂伏立诺他作为晚期BCC的候选治疗剂。随后的临床前研究表明， 伏立诺他可以抑制hedgehog信号传导和BCC细胞系和肿瘤同种异体移植物中的BCC生长。在目标1中，博士 沙林将从机制上研究HDAC 1在Hh信号传导中的作用，并进行一项2期开放标签临床试验， vorinostat治疗24例晚期BCC患者。在目标2中，Sarin博士将研究基因组学，转录组学和免疫学 与晚期基底细胞癌中的PD-1阻断相关。沙林博士得到了导师和斯坦福大学的全力支持 大学，谁是提供指导，样本，并为该建议的财政支持。成功完成本 该提案将使Sarin博士能够发展成为独立的主要研究者所需的多学科技能， 开发基于分子的皮肤癌治疗方法，并将为未来的R 01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.