Project 1: Targeting autophagy for the treatment of KRAS-mutant PDAC

项目1：靶向自噬治疗KRAS突变型PDAC

基本信息

批准号：
10334083
负责人：
CHANNING J. DER
金额：
$ 46.76万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10334083
关键词：
Acute Aftercare Automobile Driving Autophagocytosis BRAF gene Biological Markers Biopsy CRISPR/Cas technology Caring Cells Chronic Clinical Clinical Trials Combined Modality Therapy Cytostatics Development Eating Evaluation Future Gene Expression Genes Genetic Genome Genomic Library Glycolysis Goals Growth Growth Inhibitors Hydroxychloroquine Hypersensitivity Immune Immune response Impairment KRAS2 gene Lead MEK inhibition MEKs Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Metabolism Mitochondria Mitogen-Activated Protein Kinases Modeling Mus Mutation Normal tissue morphology Nutrient Oncology Organelles Organoids Paclitaxel Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phase II Clinical Trials Phenocopy Pre-Clinical Model Process Protein Kinase Publishing Randomized Resistance Signal Transduction Source Toxic effect Up-Regulation advanced pancreatic cancer anti-tumor immune response arm base cancer cell clinical efficacy cytokine cytotoxic cytotoxicity effective therapy effectiveness evaluation experimental study gemcitabine genetic profiling improved inhibition of autophagy inhibitor innovation loss of function macromolecule mouse model mutant novel pancreatic cancer model pancreatic cancer patients pancreatic ductal adenocarcinoma model phase 2 study research clinical testing resistance gene resistance mechanism response response biomarker small molecule libraries standard of care targeted treatment therapeutic target therapeutically effective tumor tumorigenic

项目摘要

PROJECT 1: ABSTRACT Autophagy is a self-degradation process whereby cancer cells recycle defective organelles and macromolecules as a nutrient source to support their increased metabolic needs. Autophagy is elevated and essential for the tumorigenic growth of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC), providing the rationale for clinical evaluation of the autophagy inhibitor hydroxychloroquine (HCQ) for PDAC. Disappointingly, when used as monotherapy in combination with standard of care, HCQ has shown limited to no clinical efficacy for PDAC. We recently determined that the treatment of PDAC with inhibitors of the key KRAS effector pathway, the RAF- MEK-ERK mitogenic activated protein kinase cascade, unexpectedly caused further elevation of autophagy, rendering PDAC acutely dependent on autophagy, and hypersensitive to autophagy inhibition. We determined that ERK inhibition impaired other critical metabolic processes (glycolysis, mitochondrial function) that then led to compensatory upregulation of autophagy. Our findings, together with essentially identical conclusions by another independent co-published study, has led to our initiation of two clinical trials evaluating two approved MEK inhibitors (trametinib, binimetinib) in combination with HCQ for PDAC. Since our recent studies suggest that ERK inhibitors will have superior activity in PDAC, this has prompted our initiation of a phase II clinical trial with the ERK inhibitor LY3214996 in combination with HCQ for metastatic PDAC (Aim 1). While early observations from compassionate care utilization of this combination support a significant clinical impact for this combination, our preliminary studies (Aims 2 and 3) support our premise that we can improve upon this therapy. Aim 2 studies are based on our application of a 2,500-gene druggable genome CRISPR-Cas9 genetic-loss-of- function screen to identify genes that modulate HCQ anti-tumor activity. The identified hits that either enhance or reduce HCQ growth inhibitor activity represent candidate combinations or biomarkers for HCQ resistance, respectively. The biomarkers for response can then be applied to tumor biopsies collected in the Aim 1 clinical trial evaluation. Aim 3 studies involve our application of a chemical library screen using a 525-oncology drug set to identify combinations that enhance the cytotoxicity of HCQ. Together, combinations that arise from Aims 2 and 3 studies will then be advanced to Aim 4 studies, where we will apply PDAC organoid or orthotopic mouse tumor models to identify combinations for future clinical evaluation. Since we have found that ERK MAPK inhibition causes tumor-associated gene expression changes that can lead to an improved anti-tumor immune response, we will also evaluate the impact of our combinations on tumor cytokine expression and on tumor- associated immune cells. In summary, our studies will develop novel combination therapies to target autophagy for the treatment of KRAS-mutant PDAC.

项目 1：摘要自噬是一种自我降解过程，癌细胞回收有缺陷的细胞器和大分子作为营养来源来支持其增加的代谢需求。自噬水平升高并且对于 KRAS 突变型胰腺导管腺癌 (PDAC) 的致瘤性生长，为自噬抑制剂羟氯喹 (HCQ) 对 PDAC 的临床评价。使用时令人失望作为与标准护理相结合的单一疗法，HCQ 对 PDAC 的临床疗效有限甚至没有。我们最近确定，使用关键 KRAS 效应通路（RAF-）的抑制剂治疗 PDAC MEK-ERK 有丝分裂激活蛋白激酶级联，意外地引起自噬进一步升高，使 PDAC 严重依赖自噬，并对自噬抑制高度敏感。我们确定 ERK 抑制会损害其他关键代谢过程（糖酵解、线粒体功能），从而导致自噬的补偿性上调。我们的发现以及基本相同的结论另一项独立的共同发表的研究导致我们启动了两项临床试验，评估两项已批准的药物 MEK 抑制剂（trametinib、binimetinib）与 HCQ 联合用于 PDAC。由于我们最近的研究表明 ERK抑制剂在PDAC中具有优异的活性，这促使我们启动了II期临床试验 ERK 抑制剂 LY3214996 与 HCQ 联合治疗转移性 PDAC（目标 1）。趁早富有同情心的护理利用该组合的观察结果支持了对此的重大临床影响结合起来，我们的初步研究（目标 2 和 3）支持了我们可以改进这种疗法的前提。目标 2 研究基于我们对 2,500 个基因的可药物基因组 CRISPR-Cas9 基因缺失的应用功能筛选以鉴定调节 HCQ 抗肿瘤活性的基因。已确定的命中可以增强或降低HCQ生长抑制剂活性代表HCQ抗性的候选组合或生物标志物，分别。然后，反应的生物标志物可以应用于 Aim 1 临床中收集的肿瘤活检试用评估。目标 3 研究涉及我们使用 525 种肿瘤药物组进行化学库筛选的应用以确定增强 HCQ 细胞毒性的组合。目标 2 产生的组合在一起然后 3 项研究将推进到 Aim 4 研究，我们将应用 PDAC 类器官或原位小鼠肿瘤模型以确定未来临床评估的组合。既然我们发现 ERK MAPK 抑制引起肿瘤相关基因表达变化，从而改善抗肿瘤免疫响应，我们还将评估我们的组合对肿瘤细胞因子表达和肿瘤的影响相关的免疫细胞。总之，我们的研究将开发针对自噬的新型联合疗法用于治疗 KRAS 突变型 PDAC。