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

摘要：ras调控的RAF--mek--ERK-MAPK通路是胰腺信号转导的中枢通路。 肿瘤的发生是因为95%的胰腺癌表达突变激活的KRAS。然而，到目前为止， 在临床试验中，靶向KRAS信号的下游成分尚未显示出疗效。自噬已经 也被证明对胰腺癌的发生很重要，然而，临床试验已经被 氯喹/羟基氯喹(4-氨基喹诺酮)联合标准治疗令人失望 化疗。我们最近证明了联合抑制MEK1/2和自噬的结果 在最近发表在《自然医学》杂志上的《体外细胞毒性和体内肿瘤显著消退》一文中， 扩展到一名没有治疗选择的单一胰腺癌患者，他表现出戏剧性的 曲美替尼联合羟氯喹治疗4个月后肿瘤负担减轻~50%。二 这项工作已经产生了I/II期临床试验，并正在积累或即将开始。长期目标 作为一名内科科学家，我的研究成果是对KRAS信号做出更深层次的机械性轻描淡写 并设计成功的胰腺癌临床策略，为改善预后提供最有效的治疗方法之一 耐药的人类恶性肿瘤。这个K08应用程序的短期目标是了解阻力 曲美替尼和羟氯喹确定预测生物标志物的机制及如何克服 抵抗。我在未来5年的直接职业目标包括更新和扩大我的知识 癌症生物学，精通拨款撰写，实现本提案中概述的目标，出版 结果，帮助设计和执行工作产生的临床试验，获得拨款，继续 扩大实验室人员，产生R01应用程序，并在我的临床中建立卓越 练习一下。我的长期职业目标包括建立一家企业，调查发现 胃肠道恶性肿瘤的治疗靶点，促进对其作用的理解 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博士、G.Weldon Gilcrease III医学博士和伊格纳西奥·加里多-拉古纳医学博士。麦克马洪博士 为我提供实验室空间和RAFmekERK MAP激酶信号方面的专业知识，临床前 建模和胰腺癌细胞生物学。Gilcrease博士是一名胃肠道肿瘤学家，为临床提供指导 责任。加里多-拉古纳博士是一位胃肠道肿瘤学家，在胰腺癌和临床试验方面拥有专业知识，他 将在设计和执行预期的临床试验方面提供建议，这些试验将由这项工作产生。此外 对于这些在基础科学和临床研究方面的优秀导师，我也将得到临床前研究小组的支持 研究资源核心以及与Courtney Scaife医学博士和Jill Shea博士的合作，后者将协助 临床前模型PDX的建立和测试。总而言之，我将有一个很好的环境来推动我的事业 从事基础科学、翻译科学和临床研究方面的指导和支持工作。

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.