Targeted Modulation of the Death Receptor as a Therapeutic Strategy for Glioma

描述（由申请人提供）：该提案描述了一个5年的培训计划，旨在培养候选人成为一名成功的内科科学家和独立调查员。候选人在宾夕法尼亚大学完成了放射肿瘤学住院医师培训，并通过了放射肿瘤学委员会认证考试。现在，他将通过机构资源和指导经验的定制整合来扩展他的科学技能。该候选人具有细胞和分子生物学背景，但将从放射生物学、放射肿瘤学、分子成像、高通量筛选和实验治疗学方面的额外培训中受益匪浅。宾夕法尼亚大学和放射肿瘤科承诺全力支持拟议的职业发展计划，并通过获取和维护优秀资源和培育合作环境，为培训医师科学家提供理想的环境。这样的环境最大限度地为候选人建立一个成功的独立资助的学术生涯的潜力。因此，所描述的项目利用了艾布拉姆森癌症中心和宾夕法尼亚大学的特殊资源。艾布拉姆森癌症中心放射生物学和成像项目的共同负责人，放射肿瘤学副教授Constantinos Koumenis博士和放射肿瘤学教授兼主席Stephen M. Hahn博士将指导候选人的科学和职业发展。在一起,Drs。Koumenis和Hahn已经正式制定了一个研究计划，其中包括职业发展战略，以及一个强大的正式项目，包括定期的实验室会议、研讨会、期刊俱乐部和教学培训，以及定期安排的审查过程，以确保进展。本研究的重点是通过内质网应激和细胞凋亡外源性途径的新策略整合，为多形性胶质母细胞瘤（GBM）提供分子靶向治疗。尽管最近证明替莫唑胺（Temodar）治疗多形性胶质母细胞瘤（GBM）的疗效，但它仍然是一种无法治愈的毁灭性疾病。迫切需要新的治疗方法。该候选人已经确定了一种新的治疗机制模型，该模型整合了人GBM细胞的内质网应激和死亡受体途径，以诱导细胞凋亡。这种综合治疗策略的有效临床前验证可以作为开发基于内质网应激/细胞凋亡的靶向治疗癌症的模型。该项目与应用机械和高通量筛选方法确定癌症治疗新靶点的近期职业目标以及将这些发现转化为高级别脑肿瘤有效靶向治疗的长期职业目标相一致。博士的指导。Constantinos Koumenis和Stephen Hahn， Abramson癌症中心/宾夕法尼亚大学的独特资源和合作性质，以及Roberts质子治疗中心/Perelman高级医学中心/转化研究中心的转化临床活动，共同提供了一个特殊的环境，以支持研究项目的成功执行和候选人的职业发展。此外，该项目还整合了来自Wistar研究所和约翰霍普金斯大学的独特外部科学资源和专业知识，以提高候选人的研究和职业发展。通过完成所描述的计划，候选人将完全独立，并期望在五年内成功获得R01资助。

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the candidate's development as a Physician-Scientist and successful Independent Investigator. The candidate has completed Residency training in Radiation Oncology at the University of Pennsylvania and has passed his Radiation Oncology Board-Certification exams. He will now expand his scientific skills through a customized integration of institutional resources and mentored experiences. The candidate has a background in cell and molecular biology, but will greatly benefit from additional training in radiation biology, radiation oncology, molecular imaging, high-throughput screening, and experimental therapeutics. The University of Pennsylvania and the Department of Radiation Oncology have committed to fully support the proposed career development program and provide an ideal setting for training Physician-Scientists by acquiring and maintaining outstanding resources and nurturing a collaborative environment. Such an environment maximizes the potential for the candidate to construct a successful independently-funded academic career. The project described therefore takes advantage of the exceptional resources available at the Abramson Cancer Center and the University of Pennsylvania. Co-leaders of the Abramson Cancer Center's Radiation Biology & Imaging Program, Dr. Constantinos Koumenis, Associate Professor of Radiation Oncology and Dr. Stephen M. Hahn, Henry K. Pancoast Professor and Chair of Radiation Oncology will mentor the candidate's scientific and career development. Together, Drs. Koumenis and Hahn have formalized a research plan with a career development strategy augmented by a strong formal program that includes regular lab meetings, seminars, journal clubs and didactic training as well as a process of regularly scheduled review to ensure progress. The proposed research will focus on delivering molecular targeted therapy for Glioblastoma Multiforme (GBM) via the novel strategic integration of ER stress and the extrinsic pathway of apoptosis. Despite the recently demonstrated efficacy of temozolomide (Temodar) in treating glioblastoma multiforme (GBM), it remains an incurable and devastating disease. New therapeutic approaches are desperately needed. The candidate has identified a novel mechanistic model of therapy that integrates the ER stress and death receptor pathways in human GBM cells to induce apoptosis. Effective pre-clinical validation of this integrated therapeutic strategy could serve as a model for development of ER stress/apoptosis-based targeted therapy against cancer in general. This project aligns well with the immediate career goal of applying mechanistic and high-throughput screening approaches to identify novel targets for cancer therapy, and the long-term career goal of translating these findings into effective targeted therapy for high-grade brain tumors. The mentorship of Drs. Constantinos Koumenis and Stephen Hahn, the unique resources and collaborative nature of the Abramson Cancer Center/University of Pennsylvania, and the translational clinical activities in the Roberts Proton Therapy Center/Perelman Center for Advanced Medicine/Translational Research Center together provide an exceptional environment to support the successful execution of the research project and the career development of the candidate. Furthermore, the program incorporates unique external scientific resources and expertise from the Wistar Institute and Johns Hopkins University to enhance the candidate's research and career development. Through the completion of the program described, the candidate will proceed to full independence with the expectation of successful achievement of R01 funding within five years.