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：
10656403
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/10656403
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 Combination Drug Therapy Combined Modality Therapy Cytotoxic Chemotherapy Data Disease Doctor of Philosophy Drug Combinations Drug resistance Early Diagnosis Ectopic Expression Environment 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 Medicine Mentors Metabolism Mitogen-Activated Protein Kinases Mus Mutation Nature Oncologist Operative Surgical Procedures Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pathway interactions Patients 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 Therapeutic Intervention 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 biomarker identification c-myc Genes cancer cell cancer initiation career chemotherapy clinical investigation clinical practice comparative cytotoxic cytotoxicity design drug sensitivity efficacy evaluation genetic analysis genetic manipulation improved outcome in vivo inhibitor knock-down next generation novel therapeutic intervention overexpression pancreatic PDX models pancreatic cancer cells pancreatic cancer patients pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm patient derived xenograft model pharmacologic pre-clinical pre-clinical research predictive marker resistance mechanism response standard of care targeted treatment therapeutic target 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调节的RAFMek钱映射激酶途径是胰腺的中心途径癌症的起步为95％的胰腺腺癌表达突变激活的KRAS。但是，迄今为止在临床试验中靶向KRAS信号传导的下游成分尚未显示出有效性。自噬具有然而，也证明对胰腺癌肿瘤发生很重要，但是，临床试验一直是与标准配合使用氯喹/羟基氯喹（4-氨基喹诺酮）处理化学疗法。我们最近证明了对MEK 1/2和自噬结果的联合抑制在自然医学的最新出版物中，体外细胞毒性和体内肿瘤回归的戏剧性被扩展到单个胰腺癌患者，没有剩下的治疗选择，这些患者表现出戏剧性在4个月治疗曲美替尼和羟氯喹后4个月后，肿瘤烧伤减少了约50％。二 I/II阶段的临床试验是由工作引起的，要么即将开放或开放。长期目标我作为物理科学家的研究是为了贡献更深的机械，低估了Kras信号传导胰腺癌和设计成功的临床策略，以改善最治疗方法之一抵抗人类恶性肿瘤。该K08应用的短期目标是了解抵抗曲线替尼和羟基氯喹的机制，以确定预测性生物标志物以及如何克服反抗。我未来5年的职业目标包括更新和扩大我对癌症生物学，精通赠款写作，完成此提案中概述的目标，出版结果，有助于设计和执行由工作导致的临床试验，获得赠款，继续扩展实验室人员，生成R01应用程序并在我的临床上建立卓越实践。我的长期职业目标包括建立调查的企业治疗胃肠道恶性肿瘤的治疗靶点，进一步了解了对角色的理解领域自噬在恶性肿瘤中，并培训下一代的医生和科学家。我的导师包括 Martin McMahon博士，G。WeldonGilcrese III，医学博士和Ignacio Garrido-Laguna，医学博士。麦克马洪博士为我提供RAF的实验室空间和专业知识，MekERKMAP激酶信号，前临床前建模和胰腺癌细胞生物学。 Gilcrease博士是GI肿瘤学家提供临床指导责任。 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，他将建议设计和执行这项工作的预期临床试验。此外对于这些基础科学和临床追求的优秀导师，我也将得到临床前的支持研究资源核心以及与医学博士Courtney Scaife和Jill Shea的合作，他们将协助协助临床前模型PDX建立和测试。总而言之，我将有一个很好的环境来进一步在基础科学，转化科学和临床研究的指导和支持的职业中。