Resistance Mechanisms to Combined Trametinib and 4-aminoquinolones in the Inhibition of Pancreatic Cancer

翻译后摘要：RAS调节的RAF-ERK-ERK-MAP激酶途径是胰腺癌的中心途径， 95%的胰腺癌表达突变激活的KRAS。然而，迄今为止， 在临床试验中靶向KRAS信号传导的下游组分没有显示出功效。自噬 也被证明对胰腺癌肿瘤发生很重要，然而，临床试验已经被证实， 氯喹/羟氯喹（4-氨基喹诺酮类）与标准联合治疗令人失望 化疗我们最近已经证明，联合抑制MEK 1/2和自噬导致 体外细胞毒性和显著的体内肿瘤消退， 扩展到一个没有治疗选择的胰腺癌患者， 曲美替尼和羟氯喹联合治疗4个月后，肿瘤负荷降低约50%。两 I/II期临床试验已经从这项工作中产生，并且正在积累或即将开放。远景目标 作为一名物理学家，我的研究的一个重点是对KRAS信号的更深层次的机制性理解， 胰腺癌和设计成功的临床策略，以改善结果的最治疗之一， 耐药的人类恶性肿瘤。本K 08应用程序的短期目标是了解阻力 曲美替尼和羟氯喹的机制，以确定预测性生物标志物以及如何克服 阻力我在未来5年的职业目标包括更新和扩大我的知识， 癌症生物学，精通赠款写作，完成本提案中概述的AIMS，出版 结果，协助设计和执行临床试验的工作，获得赠款，继续 扩大实验室人员，生成R 01应用程序，并在我的临床实践中建立卓越 实践我的长期职业目标包括建立一个企业的调查发现 用于治疗胃肠道恶性肿瘤的治疗靶点，进一步了解 恶性肿瘤中的自噬，以及培养下一代医生和科学家。我的导师包括 Martin McMahon，PhD，G. Weldon Gilcrease III，医学博士和伊格纳西奥Garrido-Laguna，医学博士，博士。麦克马洪医生 为我提供了实验室空间和RAF ERK ERK MAP激酶信号传导，临床前 建模和胰腺癌细胞生物学。Gilcrease博士是一名GI肿瘤学家， 责任Garrido-Laguna博士是一名GI肿瘤学家，在胰腺癌和临床试验方面具有专业知识， 将建议在设计和执行预期的临床试验，将导致从这一机构的工作。此外 这些优秀的导师在基础科学和临床的追求，我也将支持临床前 研究资源核心和合作与考特尼斯凯夫，医学博士和吉尔谢伊，博士谁将协助 临床前模型PDX的建立和测试。总之，我将有一个很好的环境，以进一步我的 职业生涯与指导和支持基础科学，转化科学和临床研究。

Abstract: The RAS-regulated RAFMEKERK MAP kinase pathway is a central pathway for pancreatic cancer initiation as 95% of pancreatic adenocarcinomas express mutationally activated KRAS. To date, however, targeting downstream components of KRAS signaling in clinical trials have not shown efficacy. Autophagy has also been shown to be important for pancreatic cancer tumorigenesis, however, clinical trials have been disappointing with chloroquine/hydroxychloroquine (4-aminoquinolones) treatment in conjunction with standard chemotherapy. We have recently demonstrated that combined inhibition of both MEK 1/2 and autophagy results in in vitro cytotoxicity and dramatic in vivo tumor regression in a recent publication in Nature Medicine, which was extended to a single pancreatic cancer patient with no therapeutic options left who demonstrated a dramatic tumor burden reduction of ~50% after 4 months of therapy of combined trametinib and hydroxychloroquine. Two Phase I/II clinical trials have resulted from the work and are either accruing or soon to open. The long-term goals of my research as a physician-scientist is to contribute a deeper mechanistic understating of KRAS signaling in pancreatic cancer and design successful clinical strategies to improve outcomes for one of the most treatment resistant human malignancies. The short-term goals of this K08 application are to understand the resistance mechanisms to trametinib and hydroxychloroquine to determine predictive biomarkers and how to overcome resistance. My immediate career goals over the next 5 years include updating and broadening my knowledge of cancer biology, becoming proficient in grant writing, accomplishing the AIMS outlined in this proposal, publishing the results, assisting in designing and executing clinical trials resulting from the work, securing grants, continued expansion of laboratory personnel, generating R01 applications, and establishing excellence in my clinical practice. My long term career goals include building an enterprise of investigations into the discovery of therapeutic targets for treating gastrointestinal malignancies, furthering the field of understanding of the role for autophagy in malignancy, and training the next generation of physicians and scientists. My mentors include Martin McMahon, PhD, G. Weldon Gilcrease III, MD and Ignacio Garrido-Laguna, MD, PhD. Dr. McMahon provides me with laboratory space and expertise in RAFMEKERK MAP kinase signaling, pre-clinical modeling and pancreatic cancer cell biology. Dr. Gilcrease is a GI Oncologist provides guidance with clinical responsibilities. Dr. Garrido-Laguna is a GI Oncologist with expertise in pancreatic cancer and clinical trials, who will advise in designing and executing anticipated clinical trials that will result from this body of work. In addition to these excellent mentors in basic science and clinical pursuits I will also have the support of the Preclinical Research Resource Core and collaboration with Courtney Scaife, MD and Jill Shea, PhD who will assist with preclinical model PDX establishment and testing. In summary I will have an excellent environment to further my career with guidance and support for basic science, translational science, and clinical investigation.