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

• 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
• 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

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 作为支持其代谢需求增加的营养来源。自噬升高，对于 Kras突变胰腺导管腺癌（PDAC）的致瘤性生长，提供了理由 PDAC的自噬抑制剂羟氯喹（HCQ）的临床评估。令人失望的是，当使用时 作为单一疗法与标准护理相结合，HCQ已显示出PDAC的临床疗效不限。 我们最近确定了用关键KRAS效应途径抑制剂（RAF-）对PDAC进行处理 MEK-ERK有丝分裂激活的蛋白激酶级联反应意外导致自噬的进一步升高， 使PDAC急性依赖于自噬，并且对自噬抑制过敏。我们确定 ERK抑制作用损害了其他关键代谢过程（糖酵解，线粒体功能），然后LED 为自噬的补偿性上调。我们的发现，以及本质上相同的结论 另一项独立共同发表的研究导致我们开始了两项评估两个批准的临床试验 MEK抑制剂（Trametinib，Binimetinib）与HCQ结合使用PDAC。自从我们最近的研究表明以来 ERK抑制剂将在PDAC中具有卓越的活性，这促使我们开始了II期临床试验 与ERK抑制剂LY3214996与HCQ结合使用用于转移性PDAC（AIM 1）。早些时候 对这种组合的富有同情心护理利用的观察支持了这一重大临床影响 结合，我们的初步研究（目标2和3）支持我们可以改善这种疗法的前提。 AIM 2研究基于我们应用2500种可药的基因组CRISPR-CAS9基因遗传损害 功能屏幕以识别调节HCQ抗肿瘤活性的基因。确定的命中可以增强 或降低HCQ生长抑制剂活性代表候选组合或HCQ抗性的生物标志物， 分别。然后可以将响应的生物标志物应用于AIM 1临床中收集的肿瘤活检 试验评估。 AIM 3研究涉及我们使用525个综合药物集合化学库筛选的应用 确定增强HCQ细胞毒性的组合。共同由目标产生的组合2 然后将进行3项研究，然后进行AIM 4研究，我们将应用PDAC类器官或原位小鼠 肿瘤模型以确定将来临床评估的组合。由于我们发现Erk Mapk 抑制作用会导致肿瘤相关的基因表达变化，可导致改善的抗肿瘤免疫 反应，我们还将评估我们组合对肿瘤细胞因子表达以及肿瘤的影响 相关的免疫细胞。总而言之，我们的研究将开发出新的组合疗法以靶向自噬 用于治疗Kras突变PDAC。