RON Receptor in Pancreatic Cancer Biology and Therapy

胰腺癌生物学和治疗中的 RON 受体

基本信息

批准号：
10170276
负责人：
ANDREW M LOWY
金额：
$ 30.69万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-22 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170276
关键词：
American Antitumor Response Automobile Driving Biology Cancer Biology Cell physiology Cells Chimera organism Cytotoxic Chemotherapy Cytotoxic T-Lymphocytes Databases Development Disease Disease Progression Duct (organ) structure Epithelial Extravasation Feedback Fostering Frequencies Funding Goals Growth Heterogeneity Human Immune Immunocompetent Immunophenotyping Interleukin-10 Invaded Investigation Ionizing radiation KRAS2 gene Knock-out Laboratories Ligands Malignant neoplasm of pancreas Metaplasia Molecular Myeloid Cells Neoplasm Metastasis Neoplasms Pancreatic Ductal Adenocarcinoma Pancreatic duct Paracrine Communication Patient-Focused Outcomes Patients Pattern Phenotype Phosphotransferases Pre-Clinical Model Primary Neoplasm Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Receptor Signaling Resected Resistance Role Sampling Shapes Signal Transduction T cell response T-Cell Activation Testing The Cancer Genome Atlas Transforming Growth Factor beta Tumor-associated macrophages Work anti-tumor immune response autocrine cancer cell cancer therapy carcinogenesis chemotherapy cytokine immunomodulatory strategy improved inhibitor/antagonist lymph nodes macrophage macrophage stimulating protein mortality mouse model new therapeutic target novel therapeutic intervention overexpression pancreatic cancer cells pancreatic cancer model pancreatic cancer patients paracrine phosphatidylinositol 3-kinase gamma prevent promoter receptor recombinase response therapy resistant treatment response tumor tumor growth tumor microenvironment tumor progression wound healing

项目摘要

The continued rise in annual pancreatic cancer mortalities demands urgent efforts to better understand molecular mechanisms critical to tumor progression and therapeutic resistance. Our group and others identified the RON tyrosine kinase receptor as an overexpressed protein and potential novel therapeutic target in pancreatic cancer. The working hypothesis of our laboratory is that RON receptor signaling is a potent promoter of invasive growth and survival in human pancreatic cancer cells which uniquely also helps to shape the tumor microenvironment via its effects on myeloid cell function. Our recent studies demonstrate that RON signaling accelerates pancreatic duct neoplasia initiated by KRAS and that RON signaling in pancreatic cancer cells initiates a positive feedback loop driving expression of both RON itself and its cognate ligand, macrophage stimulating protein. We believe that RON signaling thereby serves to modify both epithelial and immune cell phenotypes to promote tumor growth, metastasis and therapeutic resistance. The goals of this application are; 1) to understand how autocrine/paracrine RON signaling influences primary pancreatic cancer growth, 2) determine the mechanisms by which RON signaling modifies the primary and metastatic niche to promote tumor dissemination and metastatic outgrowth, and 3) to test RON inhibition as an immunomodulatory strategy in preclinical models of pancreatic cancer. The findings from these studies will enhance our understanding of RON biology and thereby serve to inform the development and further testing of RON- directed therapies in pancreatic cancer.

每年胰腺癌死亡率持续上升，需要紧急努力更好地了解对肿瘤进展和治疗耐药至关重要的分子机制。我们组和其他人确定 RON 酪氨酸激酶受体是一种过度表达的蛋白质和潜在的新治疗靶点在胰腺癌中。我们实验室的工作假设是 RON 受体信号传导是一种有效的人类胰腺癌细胞侵袭性生长和存活的促进剂，这也独特地有助于塑造通过其对骨髓细胞功能的影响来调节肿瘤微环境。我们最近的研究表明 RON 信号传导加速胰腺癌中 KRAS 和 RON 信号传导引发的胰管肿瘤形成细胞启动正反馈循环，驱动 RON 本身及其同源配体的表达，巨噬细胞刺激蛋白。我们相信 RON 信号传导从而可以修饰上皮细胞和免疫细胞表型促进肿瘤生长、转移和治疗耐药性。本次活动的目标应用程序是； 1) 了解自分泌/旁分泌 RON 信号如何影响原发性胰腺癌生长，2) 确定 RON 信号传导修饰原发性和转移性微环境的机制促进肿瘤扩散和转移生长，3) 测试 RON 抑制作为免疫调节剂胰腺癌临床前模型的策略。这些研究的结果将增强我们的了解 RON 生物学，从而为 RON- 的开发和进一步测试提供信息胰腺癌的定向治疗。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Efficacy of dimethylaminoparthenolide and sulindac in combination with gemcitabine in a genetically engineered mouse model of pancreatic cancer.

二甲氨基小白菊内酯和舒林酸联合吉西他滨在胰腺癌基因工程小鼠模型中的疗效。

DOI：
发表时间：
2013-01
期刊：
影响因子：
2.9
作者：
Yip;Wu, Huangbing;Hruban, Ralph H;Lowy, Andrew M;Crooks, Peter A;Schmidt, Christian Ma
通讯作者：
Schmidt, Christian Ma

The MST1R/RON Tyrosine Kinase in Cancer: Oncogenic Functions and Therapeutic Strategies.

癌症中的 MST1R/RON 酪氨酸激酶：致癌功能和治疗策略。

DOI：
发表时间：
2022-04-18
期刊：
影响因子：
5.2
作者：
Cazes, Ale;Childers, Betzaira G;Esparza, Edgar;Lowy, Andrew M
通讯作者：
Lowy, Andrew M

A MET Targeting Antibody-Drug Conjugate Overcomes Gemcitabine Resistance in Pancreatic Cancer.

MET 靶向抗体药物偶联物克服了胰腺癌中的吉西他滨耐药性。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Cazes, Ale;Betancourt, Oscar;Esparza, Edgar;Mose, Evangeline S;Jaquish, Dawn;Wong, Eric;Wascher, Alexis A;Tiriac, Hervé;Gymnopoulos, Marco;Lowy, Andrew M
通讯作者：
Lowy, Andrew M

FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine.

FRAX597 是一种 PAK1 抑制剂，与吉西他滨联合使用可协同减少胰腺癌的生长。