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Chemotherapy-driven evolution of the vascular secretome and its role in therapeutic resistance

化疗驱动的血管分泌组进化及其在治疗抵抗中的作用

基本信息

批准号：
10544717
负责人：
Cyrus M Ghajar
金额：
$ 39.45万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544717
关键词：
Adjuvant Affect Animals Benchmarking Blood Vessels Bone Marrow Brain Breast Cancer Cell Breast Cancer Patient Breast Cancer Prevention Breast cancer metastasis Cell Cycle Cell Survival Cell Therapy Cells Chemoprotective Agent Cytoprotection DNA Damage Data Distant Endothelial Cells Endothelium Estrogen receptor positive Evolution Future Goals Individual Integrin Inhibition Integrins Left Ligands Liver Lung Measures Mediating Metastatic Neoplasm to the Bone Modeling Mus Mutagens NTN1 gene Neoplasm Metastasis Output Patients Phase Pre-Clinical Model Primary Neoplasm Protein Array Recurrence Regimen Resistance Risk Role Safety Signal Pathway Signal Transduction Site Source Stereotyping Stress Testing Therapeutic Tissues Toxic effect Transgenic Organisms Translating Up-Regulation Vascular Cell Adhesion Molecule-1 Vascular Endothelium Vertebral column Work ataxia telangiectasia mutated protein breast cancer survival chemotherapy extracellular genotoxicity hormone therapy improved in vivo innovation knock-down malignant breast neoplasm metastasis prevention neoplastic cell novel novel strategies pre-clinical prevent protective factors response sensor stem synergism targeted treatment therapy resistant vascular factor von Willebrand Factor

项目摘要

PROJECT SUMMARY Our continued inability to develop selective therapies that prevent the emergence of disseminated breast tumor cells into lethal metastases necessitates new approaches. We have shown that disseminated tumor cells (DTCs) occupy the perivascular niche (PVN), that this niche promotes chemotherapeutic resistance, and that targeting interactions between DTCs and the PVN sensitizes DTCs to chemotherapy. Translating this approach to pre-clinical models of breast cancer prevented metastases in over 60% of at-risk mice. Questioning the mechanism(s) of resistance in the remainder of mice led us to consider the dynamic response of the vascular niche to chemotherapy. Our preliminary data indicate that genotoxic agents trigger the secretion of pro-survival factors into the PVN, and that the major trigger of this chemotherapy-associated vascular secretome is the DNA damage response (DDR). Therefore, here our goal is to target the cause (i.e., the DDR) and the consequence (i.e., the chemotherapy-associated vascular secretome) of vascular evolution, which we suspect promotes therapeutic resistance of DTCs. We will pursue this goal through 2 specific aims: Specific Aim 1. To determine whether individual extracellular factors elicited from vascular endothelium by chemotherapy protect DTCs. We have defined a global vascular response to DNA damaging agents. Netrin-1 is a prominent component of this secretome with documented pro-survival functions. Our data show that endo- thelial-derived Netrin-1 protects DTCs from chemotherapy. Using organotypic, transgenic and preclinical mod- els, we will determine: i) whether endothelial cells are the relevant source of chemotherapy-elicited Netrin-1 in vivo; ii) whether targeting Netrin-1 as an adjuvant sensitizes DTCs to chemotherapy; iii) whether this syner- gizes with targeting pre-existing protective factors in the PVN; and iv) the safety of these approaches. Specific Aim 2. To identify DNA damage driven signaling pathways in vascular endothelium that induce the chemotherapy-associated vascular secretome. Our preliminary data demonstrate that genotoxic therapy elicits a stereotypic DDR from quiescent endothelium, and that targeting a nucleator of this response mutes the ma- jority of the chemotherapy-associated vascular secretome. This approach may be a more robust alternative to targeting a single pro-survival factor such as Netrin-1. Here, we will identify and target the signaling pathway that connects DDR to the vascular secretome, and measure the efficacy and toxicity of this approach. The significance and innovation of this work lie in the discovery of origins and outputs of chemoprotective factors in the DTC niche. Targeting both will result in the first approach to specifically target DTCs, impacting breast cancer survival in a positive and lasting fashion.

项目总结