Duke SPORE in Brain Cancer

描述（由申请人提供）：恶性原发性脑肿瘤是儿童和年轻人癌症死亡的最常见原因，死亡人数超过肾癌或黑色素瘤。此外，目前的治疗是失能性的，并且受到非特异性毒性的限制。尽管进行了数百次临床试验，但在上个世纪，只有少数药物被批准用于临床。因此，目前的脑肿瘤治疗方法是美国目前提供的每质量调整生命年节省的最昂贵的药物治疗方法。尽管如此，在这个应用程序中处理的肿瘤仍然是致命的。杜克脑癌孢子是一个跨学科的研究计划，将利用脑肿瘤生物学的知识，以快速的方式开发多种治疗成人原发性脑肿瘤的新方法，以便对癌症死亡率和发病率产生直接影响。反过来，这个孢子将决定在这些患者群体中观察的生物学基础，以改善这些治疗方法。该应用程序利用一组具有悠久合作历史和成功转化研究的资深科学家和医生科学家，通过整合新的杜克癌症研究所，并仔细评估和监测4个项目，4个核心和2个计划，专注于吸引新的和有经验的研究人员到该领域，以实现这些目标。由John Sampson和Qi-Jing Li领导的Project 1将研究EGFRvIII-嵌合抗原T细胞受体（CAR）治疗对肿瘤异质性的影响，以及在IC递送的EGFRvIII-靶向CAR的背景下，EGFRvIII-CAR转导的T细胞内miR-23a抑制是否会增强细胞毒性并赋予宿主免疫抑制的抗性。项目2由Hai Yan和John Sampson领导，将在正式的临床前毒性研究和II级或III级IDHR132H阳性胶质瘤患者的试点试验中检测针对肿瘤特异性IDH1R132H突变的肽疫苗的安全性。项目3由Michael Zalutsky和Darell Bigner领导，将评估2111atlabeled anti-tenascin MAb 81C6在新诊断的GBM患者中的治疗潜力。由Matthias Gromeier和Allan Friedman领导的项目4将对一种有前景的溶瘤性脊髓灰质炎病毒进行临床试验，并阐明这种疗法产生抗肿瘤免疫反应的机制。每个项目都将被频繁地评估，如果没有达到它的翻译目标就会被替换。这些项目将由4个核心提供行政支持（核心A）；生物统计学、信息学和数据协调资源（核心B）；临床试验操作基础设施（核心C），生物标本，病理学和免疫监测专业知识（核心D）。将强调杜克大学内部、与其他孢子、政府和非政府组织的合作，以促进孢子研究沿着转化科学连续体的横向和纵向运动。

DESCRIPTION (provided by applicant): Malignant primary brain tumors are the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Moreover, current therapy is incapacitating and limited by non-specific toxicity. Despite hundreds of clinical trials, only a handful of agents have been approved for use in the clinic in the last century. As a result, current therapy for brain tumors represents the mos expensive medical therapy per quality-adjusted life-year saved currently provided in the US. Despite all of this, the tumors addressed in this application remain uniformly lethal. The Duke SPORE in Brain Cancer is an interdisciplinary research proposal that will use knowledge of brain tumor biology to develop diverse new approaches to the treatment of adult primary brain tumors in an expeditious fashion in order to have an immediate impact on cancer mortality and morbidity. In turn, this SPORE will determine the biological basis for observations made in these patient populations in order to improve these treatments. This application leverages a group of senior scientists and physician-scientists with a long history of collaboration and successful translational research to accomplish these goals through integration within the new Duke Cancer Institute and careful evaluation and monitoring of 4 Projects, 4 Cores and 2 Programs focused on attracting new and experienced investigators to this field. Project 1, led by John Sampson and Qi-Jing Li, will examine the impact of EGFRvIII-chimeric antigen T-cell receptor (CAR) therapy on tumor heterogeneity and whether miR-23a inhibition within EGFRvIII-CAR transduced T cells enhances cytotoxicity and confers resistance to host immunosuppression in the context of an IC delivered EGFRvIII- targeted CAR. Project 2, led by Hai Yan and John Sampson, will examine the safety of a peptide vaccine targeting the tumor-specific IDH1R132H mutation in formal preclinical toxicity studies and a pilot trial in patients with grade II or III IDHR132H positive glioma. Project 3, led by Michael Zalutsky and Darell Bigner, will evaluate the therapeutic potential of 211Atlabeled anti-tenascin MAb 81C6 in newly diagnosed GBM patients. Project 4, led by Matthias Gromeier and Allan Friedman, will conduct a clinical trial wit a promising oncolytic poliovirus and elucidate mechanisms by which this therapy generates an anti-tumor immune response. Each project will be evaluated frequently and replaced if not meeting its translational goals. The projects will be supported by 4 Cores that provide Administrative support (Core A); Biostatistics, Informatics, and Data Coordination resources (Core B); Clinical Trial Operations infrastructure (Core C), and Biospecimen, Pathology, and Immune Monitoring expertise (Core D). Collaborations within Duke, with other SPOREs, and government and non-government organizations will be emphasized to facilitate movement of SPORE research horizontally and vertically along the translational science continuum.