A research and training program for junior clinicians in treating metastatic mela

描述(申请人提供)：此K24申请是为了支持我的职业发展，因为我建立了一个翻译研究项目。我是一名副教授，负责治疗黑色素瘤和肾癌患者。我指导初级教员和临床研究员，并运营一个由R-01资助的研究实验室，对这两种疾病进行生物标记物研究和临床前药物测试实验。我有一个忙碌的临床实践，积极地招募病人参加临床试验。鉴于转移性黑色素瘤发病率的增加和脑转移(BRMS)的高频率，迫切需要新的方法来解决这个问题，因为大多数临床试验排除了BRMS患者，而且他们的治疗选择极其有限。我最近召集了一群专注于BRMS的临床和基础科学研究人员，我的愿景(和长期目标)是在耶鲁大学建立一个脑转移研究中心。我的短期目标是执行我们的前两个特定于BRMS的方案，并为未来的试验生成临床前数据。为了实现我的目标，我需要额外的保护时间来进行这些研究，并指导初级临床医生参与这些努力。我提出的职业发展计划既包括获得新技能，也包括增加初级教员和临床研究员的指导。前者包括正规培训，如讲授统计学课程和动物实验的非正式培训，以及开发第一阶段试验的额外培训。除了指导研究员，我还将指导初级教职员工，包括两名现有的受训者和两名新员工。我将参加由CTSA资助的耶鲁大学的具体辅导活动，包括咨询委员会和讲座。这一提议的基本前提是，药物通过BRMS中发现的泄漏血管的渗透可以优于典型的血脑屏障渗透。我们进一步假设，使用基于个别肿瘤特征选择的局部治疗和分子靶向治疗的组合将导致BRMS患者的生存率提高，与其他内脏转移患者类似。最后，操纵大脑免疫可能是治疗脑转移瘤的一种手段。我的第一个目标包括使用靶向治疗(Vemurafenib)和创新的外科方法来治疗无法接受伽玛刀治疗的脑转移瘤患者的第一个新辅助临床试验。预测性生物标记物研究将被纳入，同时以实验室为基础的努力培训受试者进行临床前药物敏感性研究，重点是BRMS，目标是开发一条在未来BRM试验中研究的药物流水线。在《目标2》中，我将指导一名低年级学生 学院临床医生，进行针对免疫检查点抑制分子(PD-1)的抗体的临床试验，并开发一组预测生物标记物。

DESCRIPTION (provided by applicant): This K24 application is to support my career development as I build a translational research program. I am an associate professor, seeing patients with melanoma and renal cell carcinoma. I mentor junior faculty and clinical fellows and run an R-01 funded research laboratory, conducting biomarker studies and pre-clinical drug testing experiments in these two diseases. I have a busy clinical practice and actively enroll patients on clinical trials. Given the increased incidence of metastatic melanoma and the high frequency of brain metastases (BrMs) in this population, there is urgent need for new approaches to this problem, as most clinical trials exclude BrMs patients, and their therapeutic options are exceedingly limited. I recently assembled a group of clinical and basic science researchers that focus on BrMs, and my vision (and long term goal) is to develop a brain metastasis research center at Yale. My short term goal is to conduct our first two BrMs-specific protocols and to generate preclinical data for future trials. To accomplish my goals, I need additional protected time to conduct these studies and mentor junior clinicians to participate these efforts. My proposed career development plan includes both acquisition of new skills and a plan for increased mentorship of junior faculty and clinical fellows. The former involves formal training such as a didactic statistics course and informal training in animal experiments and additional training in development of phase I trials. In addition to mentorship of fellows, I will mentor junior faculty, including two current mentees and two new hires. I will participate in specific mentorship activities at Yale supported by the CTSA grant, including advisory committees and lectures. The underlying premise of this proposal is that drug penetration through the leaky vessels found in BrMs can be superior to typical BBB penetration. We further hypothesize that use of combinations of local therapies and molecular targeted therapies selected based on individual tumor characteristics will result in improved survival of patients wit BrMs, similar to patients with other visceral metastases. Finally, manipulation of brain immunity might be a means of treating brain metastases. My first aim includes the first neoadjuvant clinical trial using a targeted therapy (vemurafenib) and innovative surgical approaches to treat patients with brain metastases not amenable to gamma-knife therapy. Predictive biomarker studies will be incorporated, complimented by lab-based endeavors to train mentees in conducting pre-clinical drug sensitivity studies with an emphasis on BrMs, with the goal of developing a pipeline of drugs to be studied in future BrM trials. In aim 2, I will mentor a junior faculty clinician in conducting a clinical trial of an antibody against an immune-checkpoint inhibitory molecule (PD-1), and development of a panel of predictive biomarkers.