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Preclinical Models for Cancer Therapeutic Development

癌症治疗开发的临床前模型

基本信息

批准号：
10324176
负责人：
YOUNGKYU PARK
金额：
$ 24.8万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10324176
关键词：
Antibodies Antigens Automobile Driving Cancer Model Candidate Disease Gene Cells Data Set Desmoplastic Detection Development Disease Endothelial Cells Extracellular Matrix Fibroblasts Frequencies Genes Genetically Engineered Mouse Heterogeneity Homeostasis Human IL1R1 gene Immune Immunotherapy Inflammatory KRAS oncogenesis KRAS2 gene LIF gene Malignant Neoplasms Mitochondria Modeling Mus Mutation Oncogenes Organoids Oxidation-Reduction Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Population Pre-Clinical Model Proteomics Reporting Research Resistance Series Signal Pathway Signal Transduction Survival Rate Testing Therapeutic Viral Work cancer cell cancer type cell type design efficacy testing improved in vivo inhibitor/antagonist mouse model new therapeutic target novel novel therapeutic intervention organoid transplantation pancreatic ductal adenocarcinoma model preclinical development single-cell RNA sequencing standard of care targeted treatment therapeutic development transcriptomics tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and lethal disease due to the poor efficacy of current therapies. Therefore, my research focuses on development of preclinical models for the identification of better therapeutic strategies. Two main distinct features of PDA are the high frequency of KRAS mutations that is poorly responsive to targeted therapies and an extensive desmoplastic tumor microenvironment (TME) composed of a dense extracellular matrix (ECM), acting as a barrier to therapy, and multiple non-neoplastic cell types including cancer-associated fibroblasts (CAF), endothelial cells, and immune cells. These two prominent features of PDA contribute to its intractability to current standard-of-care, calling for tailored targeted therapies to improve patients’ survival. As we previously reported, activation of oncogenic Kras during PDA development results in alterations to redox homeostasis and mitophagy pathways, providing evidence to support a redox-targeting approach. I will employ genetically engineered mouse models (GEMMs), organoids, and organoid transplantation models of PDA to test the potential efficacy of redox therapies, in particular mitochondrial inhibitors or ROS inducers in combination with MEKi (downstream component of Kras signaling). Our prior work has also identified heterogeneity within the population of cancer-associated fibroblasts (CAFs), each with their own distinct functions and active pathways. These fibroblasts include myofibroblastic (myCAFs), inflammatory (iCAFs) and antigen-presenting (apCAFs) CAFs. Understanding the underlying mechanisms of their active pathways is necessary for the development of therapeutic strategies to ablate tumor- promoting fibroblasts specifically. We reported that JAKi shifted the CAF subtypes towards myCAFs and suppressed tumor growth. I continue to target other active iCAF-signaling pathways through IL1R antagonism or delivery of anti-LIF antibodies in combination with immunotherapy using our GEMM models. Understanding how different types of CAFs contribute to tumor growth will provide a new avenue to develop strategies to ablate the cancer cell-promoting CAFs. To this end, we will uncover the identities and functions of these CAFs in our novel intraductally engrafted human organoid (IGO) model using a single-cell RNA sequencing approach. I will establish a series of IGO models with patient-derived organoids and use these mice to test the efficacy of co- targeting cancer cells and cancer-promoting CAFs by applying the findings from scRNA-seq analysis. Lastly, I will develop viral-induced GEMMs of PDA that can serve as a rapid platform to investigate the importance of candidate genes identified in our transcriptomic or proteomic datasets derived from our organoid and mouse models. Taken together, these multiple approaches I will employ to studying PDA, its primary driving oncogene and aberrantly altered pathways, and the surrounding microenvironment will elucidate key pathways the cancer cells require with the potential of these pathways acting as new therapeutic targets.

项目总结/文摘