Resistance to Cancer Therapeutics Through Microenvironment Damage Responses.

描述（由申请人提供）：虽然大多数晚期实体瘤最初对遗传毒性化疗和/或放疗有反应，但耐药的发展很常见，预示着不良结局。 该提案将检验以下假设：由癌症治疗剂诱导的组织微环境中的DNA损伤通过由非肿瘤驻留细胞类型决定的细胞非自主机制促进有害的肿瘤细胞表型（治疗抗性）。 我们进一步假设，抑制这种DNA损伤分泌程序（DDSP）的特定组分将减弱治疗抗性并增强肿瘤反应。 我们建议通过三个具体目标来检验这一假设。 目的1将确定特异性旁分泌作用DNA损伤分泌程序（DDSP）蛋白调节不良肿瘤细胞行为（例如治疗抗性）的能力，并确定它们这样做的机制。 目的2将确定差异调节包括DDSP的效应蛋白亚群的细胞内信号转导程序。 目标3将确定不同肿瘤类型之间DDSP的一致性，并建立损伤反应程序的时间和细胞类型特异性变异性。 这些目标的成功完成将改变目前对遗传毒性和途径导向（例如EGFR）治疗的治疗抗性概念，将重点从内在肿瘤细胞改变（罕见的克隆选择性事件）转移到对肿瘤细胞表型的背景依赖性（遗传毒性损伤）微环境影响。 确定DDSP促进治疗抗性的机制将为共靶向特定DDSP组分和/或其调节节点以减轻促进内在肿瘤细胞抗性程序（例如EMT）和集体效应（例如增强的肿瘤细胞再增殖动力学）的微环境信号提供基本原理。

DESCRIPTION (provided by applicant): Though most advanced solid tumors initially respond to genotoxic chemotherapy and/or radiation, the development of resistance is common and portends a poor outcome. This proposal will test the hypothesis that DNA damage in the tissue microenvironment, induced by cancer therapeutics, promotes detrimental tumor cell phenotypes (therapy resistance) through cell non-autonomous mechanisms dictated by non-neoplastic resident cell types. We further hypothesize that inhibiting specific components of this DNA damage secretory program (DDSP) will attenuate therapy resistance and enhance tumor responses. We propose to test this hypothesis through three specific aims. Aim 1 will determine the ability of specific paracrine-acting DNA-damage Secretory Program (DDSP) proteins to modulate adverse tumor cell behaviors (e.g. therapy resistance) and determine the mechanism(s) by which they do so. Aim 2 will determine the intracellular signal transduction programs that differentially modulate subsets of effector proteins comprising DDSP. Aim 3 will determine the consistency of the DDSP across different tumor types and establish the temporal and cell type-specific variability of damage response programs. The successful completion of these aims will alter current concepts of treatment resistance, both to genotoxic and to pathway directed (e.g. EGFR) therapeutics, by shifting the emphasis from intrinsic tumor cell alterations (rare, clonally-selected events) to a context-dependent (genotoxic damage) microenvironment influence on tumor cell phenotypes. Determining the mechanisms by which the DDSP promotes therapy resistance will provide rationale for co-targeting specific DDSP components and/or their regulatory nodes to mitigate microenvironment signals that promote both intrinsic tumor cell programs of resistance (e.g. EMT) and collective effects such as enhanced tumor cell repopulation kinetics.