Therapeutic approaches that target cancer cell metabolism

描述(由申请人提供)：本提案描述了一项为期5年的计划，该计划旨在培养一名独立的临床医生和科学家，专注于对癌细胞新陈代谢的药物操纵，以改善治疗反应。该项目将由阿布拉姆森癌症中心主任克雷格·汤普森博士和宾夕法尼亚大学发展治疗主任彼得·奥德怀尔博士共同指导。这两位导师都有成功指导临床医生科学家在肿瘤学领域从事高生产率研究事业的既定记录。这一奖项将使阿马拉瓦迪博士获得生物统计学、分子技术和药代动力学建模方面的教学培训。它还将为指导培训提供受保护的时间，使应聘者能够进行一系列临床试验和实验室调查。这些研究旨在阐明癌细胞代谢的靶向成分作为治疗结果的关键决定因素的作用。癌症治疗的一个重要问题是，基于诱导细胞凋亡能力开发的治疗方法对细胞凋亡缺陷的恶性肿瘤往往无效。癌症治疗的两种非凋亡性反应是坏死和自噬。癌细胞代谢的基本特征为肿瘤细胞在全身治疗中优先经历这些过程提供了基础。该项目旨在通过完成两个特定目标来确定接受治疗的患者中的坏死和自噬的临床意义：1)将坏死、凋亡和自噬的测量与接受癌症治疗的患者的临床结果相关联；2)确定氯喹作为自噬抑制剂的抗肿瘤活性。第一个具体目标将通过应用血清ELISA、免疫组织化学和EM方法对参加晚期黑色素瘤临床试验的患者的血液和组织样本进行处理。第二个目标将是利用异种移植肿瘤模型完成羟氯喹的临床前评估，随后是羟基氯喹在难治性恶性肿瘤患者中的I期和II期临床试验。该奖项期间的多学科培训将使Amaravadi博士能够独立地为合理的药物开发做出贡献，这是NCI将最先进的癌症治疗纳入临床实践的倡议的重要组成部分。

DESCRIPTION (provided by applicant): This proposal describes a 5-year plan to develop an independent clinician-scientist focused on the pharmacological manipulation of cancer cell metabolism to improve therapeutic responses. This project will be co-mentored by Dr. Craig Thompson, Director, Abramson Cancer Center, and Dr. Peter O'Dwyer, Director, Developmental Therapeutics at the University of Pennsylvania. Both mentors have an established record of successfully mentoring clinician-scientists to highly productive research careers in oncology. This award will allow Dr. Amaravadi to obtain didactic training in biostatistics, molecular techniques, and pharmacokinetic modeling. It will also provide protected time for mentored training that will enable the candidate to conduct a series of clinical trials and laboratory investigations. These studies are designed to elucidate the role of targetable components of cancer cell metabolism as critical determinants of therapeutic outcomes. An important problem for cancer care is that therapies developed on the basis of their ability to induce apoptosis are often ineffective for malignancies with defective apoptosis. Two non-apoptotic responses to cancer therapy are necrosis and autophagy. The fundamental characteristics of cancer cell metabolism provide the basis for why cancer cells preferentially undergo these processes in response to systemic therapy. This project is designed to establish the clinical significance of necrosis and autophagy in patients undergoing therapy through the completion of two specific aims 1) To correlate measurements of necrosis, apoptosis and autophagy to clinical outcomes in patients undergoing cancer therapy, and 2) To determine the antitumor activity of chloroquine as an inhibitor of autophagy. The first specific aim will be addressed by applying a serum ELISA, immunohistochemical, and EM methods to blood and tissue samples from patients enrolled on clinical trials for advanced melanoma. The second aim will be the completion of the preclinical evaluation of hydroxychloroquine using xenograft tumor models followed by Phase I and Phase II clinical trials of hydroxychloroquine in patients with refractory malignancies. Multidisciplinary training during this award will allow Dr. Amaravadi to independently contribute to rational drug development, an important component of the NCI's initiative to incorporate state-of-the-art cancer treatments into clinical practice.