Resistance to Cancer Therapeutics Through Microenvironment Damage Responses.

描述(申请人提供)：虽然大多数晚期实体肿瘤最初对基因毒性化疗和/或放射有反应，但耐药性的发展是常见的，并预示着不良的结局。这项提议将检验这样一个假设，即癌症治疗引起的组织微环境中的DNA损伤，通过非肿瘤常驻细胞类型所决定的细胞非自治机制，促进了有害的肿瘤细胞表型(治疗抵抗)。我们进一步假设，抑制这种DNA损伤分泌程序(DDSP)的特定成分将减弱治疗抵抗并增强肿瘤反应。我们建议通过三个具体目标来检验这一假设。目的1确定特定的旁分泌作用的脱氧核糖核酸损伤分泌程序蛋白调节肿瘤细胞不良行为(如耐药)的能力，并确定其调节机制(S)。目标2将确定细胞内信号转导程序，以差异地调制组成DDSP的效应器蛋白的亚组。目的3将确定不同肿瘤类型的DDSP的一致性，并建立损伤反应程序的时间和细胞类型特定的可变性。这些目标的成功完成将通过将重点从固有的肿瘤细胞改变(罕见的克隆性选择事件)转移到上下文相关(遗传毒性损害)微环境对肿瘤细胞表型的影响，从而改变目前对基因毒性和途径导向(如EGFR)治疗耐药的概念。确定DDSP促进治疗耐药的机制将为共靶向特定的DDSP组件和/或它们的调节节点以缓解微环境信号提供理论基础，这些微环境信号既促进固有的肿瘤细胞耐药程序(例如EMT)，又促进集体效应，如增强肿瘤细胞再繁殖动力学。

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.