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

描述（由申请人提供）：本提案描述了一项为期5年的培训计划，旨在培养候选人成为一名医生-科学家和成功的独立研究者。候选人已完成在宾夕法尼亚大学放射肿瘤学住院医师培训，并已通过放射肿瘤学委员会认证考试。他现在将通过定制的机构资源和指导经验的整合来扩展他的科学技能。候选人具有细胞和分子生物学背景，但将大大受益于放射生物学，放射肿瘤学，分子成像，高通量筛选和实验治疗学的额外培训。宾夕法尼亚大学和放射肿瘤学系致力于全力支持拟议的职业发展计划，并通过获取和维护优秀的资源并营造协作环境，为培训医生-科学家提供理想的环境。这样的环境最大限度地提高了候选人构建成功的独立资助学术生涯的潜力。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领导人，放射肿瘤学副教授康斯坦丁诺斯·库梅尼斯博士和斯蒂芬·M·卡茨博士。作者：Hahn，亨利K. Pancoast教授和放射肿瘤学主席将指导候选人的科学和职业发展。Koumenis和Hahn一起正式制定了一项研究计划，其中包括一个强大的正式计划，包括定期实验室会议，研讨会，期刊俱乐部和教学培训以及定期审查以确保进展的过程。拟议的研究将集中在通过ER应激和细胞凋亡的外源性途径的新的战略整合提供分子靶向治疗多形性胶质母细胞瘤（GBM）。 尽管最近证明了替莫唑胺（Temodar）在治疗多形性胶质母细胞瘤（GBM）中的疗效，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细胞中的ER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ER应激/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来确定癌症治疗的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的有效靶向治疗的长期职业目标保持一致。Constantinos Koumenis和Stephen Hahn博士的指导，Abramson癌症中心/宾夕法尼亚大学的独特资源和协作性质，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，该计划还结合了Wistar研究所和约翰霍普金斯大学独特的外部科学资源和专业知识，以加强候选人的研究和职业发展。通过完成所描述的计划，候选人将继续完全独立，并期望在五年内成功实现R 01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.