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

初级临床医生治疗转移性黄斑变性的研究和培训计划

• 批准号: 8581535
• 负责人: Harriet M. Kluger
• 金额: $ 15.61万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581535
• 关键词: Advisory Committees; Animal Experiments; Animals; Antibodies; Autopsy; Award; BRAF gene; Basic Science; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Brain; Brain imaging; Central Nervous System Agents; Central Nervous System Diseases; Characteristics; Clinical; Clinical Sciences; Clinical Trials; Clinical Trials Design; Coupled; Data; Development; Development Plans; Disease; Drug Combinations; Drug Kinetics; Drug resistance; Electrocoagulation; Enrollment; Ethics; Faculty; Frequencies; Funding; Future; Gamma Knife Radiosurgery; Goals; Grant; Health; Immune; Immunity; Immunotherapy; In Vitro; Incidence; Individual; Investigation; Laboratories; Laboratory Research; Lasers; Lesion; Life; Local Therapy; Location; MAP Kinase Gene; Malignant Neoplasms; Mediation; Melanoma Cell; Mentors; Mentorship; Metastatic Melanoma; Metastatic malignant neoplasm to brain; Molecular Biology; Molecular Target; Neoadjuvant Study; Neoadjuvant Therapy; Neoplasm Metastasis; Neuraxis; Nursing Faculty; Oncologist; Operative Surgical Procedures; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase I Clinical Trials; Population; Principal Investigator; Process; Protocols documentation; Radiosurgery; Renal Cell Carcinoma; Reporting; Research; Research Design; Research Personnel; Research Training; Resistance; Running; Sampling; Specimen; Systemic Therapy; Techniques; Technology; Therapeutic; Therapy Clinical Trials; Time; Training; Training Programs; Translational Research; Unresectable; Visceral; Vision; Wit; Writing; base; career development; clinical practice; design; disorder control; drug development; drug sensitivity; drug testing; improved; inhibitor/antagonist; innovation; interstitial; lectures; material transfer agreement; melanoma; member; mutant; novel; novel strategies; outcome forecast; patient oriented research; patient population; pre-clinical; preclinical study; professor; programs; research study; response; skills; statistics; tool; tumor

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.

描述（由申请人提供）：此 K24 申请旨在支持我建立转化研究项目时的职业发展。我是一名副教授，负责治疗黑色素瘤和肾细胞癌患者。我指导初级教师和临床研究员，并运营一个 R-01 资助的研究实验室，对这两种疾病进行生物标志物研究和临床前药物测试实验。我的临床实践很繁忙，并积极招募患者参加临床试验。鉴于该人群中转移性黑色素瘤发病率的增加和脑转移 (BrMs) 的发生率较高，迫切需要解决这一问题的新方法，因为大多数临床试验都排除了 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 BrM 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 BrMs 特定方案并为未来的试验生成临床前数据。为了实现我的目标，我需要额外的受保护时间来进行这些研究并指导初级临床医生参与这些工作。 我提出的职业发展计划包括获得新技能和增加对初级教师和临床研究员的指导的计划。前者涉及正式培训，例如教学统计课程和动物实验方面的非正式培训以及第一阶段试验开发方面的额外培训。除了指导研究员之外，我还将指导初级教师，包括两名现任受训者和两名新员工。我将参加耶鲁大学由 CTSA 资助支持的具体指导活动，包括咨询委员会和讲座。 该提议的基本前提是药物通过 BrM 中发现的渗漏血管的渗透可以优于典型的 BBB 渗透。我们进一步假设，结合使用局部疗法和根据个体肿瘤特征选择的分子靶向疗法将提高 BrM 患者的生存率，类似于其他内脏转移的患者。最后，操纵大脑免疫可能是治疗脑转移的一种手段。我的第一个目标包括首次使用靶向治疗（维莫非尼）和创新手术方法进行新辅助临床试验，以治疗不适合伽马刀治疗的脑转移患者。将纳入预测性生物标志物研究，并辅以基于实验室的努力，培训受训者进行临床前药物敏感性研究，重点是 BrM，目标是开发一系列在未来 BrM 试验中研究的药物。在目标 2 中，我将指导一名初级学生 教授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志物。