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基因毒性化疗和/或放疗有反应，但耐药性的发展是常见的，预示着预后不佳。该提案将验证由癌症治疗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肿瘤细胞表型（治疗抗性）的假设。我们进一步假设，抑制这种DNA损伤分泌程序（DDSP）的特定成分将减轻治疗耐药性并增强肿瘤反应。我们建议通过三个具体目标来检验这一假设。目的1将确定特定旁分泌作用dna损伤分泌程序（DDSP）蛋白调节肿瘤细胞不良行为（如治疗耐药性）的能力，并确定其机制。目的2将确定细胞内信号转导程序，这些程序对包含DDSP的效应蛋白亚群进行差异调节。目的3将确定DDSP在不同肿瘤类型中的一致性，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通过将重点从肿瘤细胞内在改变（罕见的，克隆选择事件）转移到环境依赖性（基因毒性损伤）微环境对肿瘤细胞表型的影响，改变目前对基因毒性和途径导向（例如EGFR）治疗的治疗耐药性概念。确定DDSP促进治疗耐药的机制将为共同靶向特定DDSP成分和/或其调控节点提供理论依据，以减轻微环境信号，这些微环境信号促进了肿瘤细胞固有的耐药程序（如EMT）和集体效应，如增强肿瘤细胞再生动力学。

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. PUBLIC HEALTH RELEVANCE: The tumor microenvironment (TME) is increasingly recognized as a major contributor to the development and progression of malignant neoplasms. We propose to evaluate the original concept that conventional cancer therapeutics, such as ionizing radiation and alkylating drugs, which exert anti-tumor effects through DNA damage, modify the TME to enhance resistance to subsequent treatments, and consequently promote adverse cancer phenotypes.