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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：
10705570
负责人：
CHANNING J. DER
金额：
$ 41.52万
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/10705570
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 Immune Immune response Impairment KRAS2 gene 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 Phase II Clinical Trials Phenocopy Pre-Clinical Model Process Protein Kinase Publishing Randomized Recycling Resistance Signal Transduction Source Toxic effect Up-Regulation advanced pancreatic cancer anti-tumor immune response arm 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 pharmacologic 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.

项目一：摘要