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

曲美替尼联合 4-氨基喹诺酮类药物抑制胰腺癌的耐药机制

基本信息

批准号：
10437778
负责人：
Conan Kinsey
金额：
$ 27.29万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437778
关键词：
Autophagocytosis Back Basic Science Biochemical Process Biochemistry Biology Biopsy Specimen Bromodomain Bypass CDK4 gene CRISPR/Cas technology Cancer Biology Cancer Etiology Cancer cell line Cell Cycle Cell Line Cells Cellular Assay Cellular Metabolic Process Cellular biology Cessation of life Chloroquine Clinical Clinical Trials Collaborations Combined Modality Therapy Cytotoxic Chemotherapy Data Disease Doctor of Philosophy Drug Combinations Drug resistance Early Diagnosis Ectopic Expression Environment Extracellular Signal Regulated Kinases FDA approved Genetic Goals Grant Growth Human Hydroxychloroquine In Vitro Investigation KRAS2 gene Knowledge Laboratories Laboratory Personnel Lead Left MEKs Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of pancreas Mass Spectrum Analysis Measures Mediating Mediator of activation protein Medicine Mentors Metabolism Mitogen-Activated Protein Kinases Modeling Mus Mutation Nature Oncologist Operative Surgical Procedures Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmacology Phase Phase I/II Clinical Trial Phosphotransferases Physicians Play Pre-Clinical Model Precision therapeutics Prevention Process Proteins Publications Publishing Ras Signaling Pathway Recycling Reporter Research Resistance Resources Retinoblastoma Genes Role STK11 gene Scientist Secure Signal Transduction System Testing Therapeutic Toxic effect Training Translational Research Translations Tumor Burden Tumor Markers Tumor Tissue Update Work Writing Xenograft Model Xenograft procedure advanced pancreatic cancer antitumor effect aurora kinase A c-myc Genes cancer cell cancer clinical trial cancer initiation career chemotherapy clinical investigation clinical practice comparative cytotoxic cytotoxicity design genetic analysis genetic manipulation improved outcome in vivo inhibitor knock-down next generation overexpression pancreatic PDX models pancreatic cancer cells pancreatic cancer patients pancreatic ductal adenocarcinoma cell pancreatic neoplasm patient derived xenograft model pre-clinical pre-clinical research predictive marker resistance mechanism response standard of care targeted treatment therapeutic target treatment strategy tumor tumor metabolism tumor xenograft tumorigenesis

项目摘要

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.

摘要: RAS调控的RAFMEKERK MAP激酶通路是胰腺癌的中枢通路。 95% 的胰腺腺癌表达突变激活的 KRAS，从而引发癌症。然而，迄今为止，临床试验中针对 KRAS 信号下游成分的药物尚未显示出疗效。自噬有也被证明对胰腺癌肿瘤发生很重要，然而，临床试验已证实氯喹/羟氯喹（4-氨基喹诺酮类）联合标准治疗令人失望化疗。我们最近证明，MEK 1/2 和自噬的联合抑制会产生在《自然医学》最近发表的一篇文章中，研究了体外细胞毒性和体内肿瘤显着消退，其中扩展到一名没有治疗选择的胰腺癌患者，该患者表现出戏剧性的效果曲美替尼和羟氯喹联合治疗 4 个月后，肿瘤负荷减少约 50%。二 I/II 期临床试验已经取得成果，并且正在积累或即将开始。长期目标作为一名医师兼科学家，我的研究目标是对 KRAS 信号转导机制有更深入的理解胰腺癌并设计成功的临床策略以改善最有效治疗方法之一的结果抵抗人类恶性肿瘤。该 K08 应用程序的短期目标是了解电阻曲美替尼和羟氯喹确定预测生物标志物的机制以及如何克服反抗。我未来 5 年的近期职业目标包括更新和拓宽我的知识癌症生物学，精通资助写作，实现本提案中概述的目标，出版结果，协助设计和执行工作产生的临床试验，获得资助，继续扩大实验室人员，生成 R01 应用程序，并在我的临床领域建立卓越的表现实践。我的长期职业目标包括建立一家研究发现的企业治疗胃肠道恶性肿瘤的治疗靶点，进一步加深了对其作用的理解恶性肿瘤中的自噬，并培训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 Ignacio Garrido-Laguna 医学博士、博士。麦克马洪博士为我提供了 RAFMEKERK MAP 激酶信号传导、临床前的实验室空间和专业知识建模和胰腺癌细胞生物学。 Gilcrease 博士是一位胃肠道肿瘤学家，提供临床指导责任。 Garrido-Laguna 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，将就设计和执行这项工作所产生的预期临床试验提供建议。此外感谢这些基础科学和临床研究方面的优秀导师，我还将得到临床前研究团队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，他们将协助临床前PDX模型的建立和测试。总而言之，我将有一个良好的环境来进一步发展我的事业。为基础科学、转化科学和临床研究提供指导和支持的职业生涯。