A sequential therapeutic strategy of senescence induction and senolytics for elimination of surviving residual breast tumor cells

衰老诱导和衰老抑制剂的序贯治疗策略，用于消除存活的残留乳腺肿瘤细胞

• 批准号: 10360542
• 负责人: David A. Gewirtz
• 金额: $ 49.92万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360542
• 关键词: Aftercare; Animals; Antigens; Antitumor Response; Apoptosis; Apoptotic; BCL1 Oncogene; BCL2 gene; BCL2L1 gene; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Cell Culture Techniques; Cell Death; Cells; Characteristics; Chemotherapy and/or radiation; Clinic; Clinical Trials; Cross Presentation; Cytolysis; Data; Disease; Dose; Effectiveness; Exposure to; Goals; Growth; Human; Immune; Immune response; Immune system; Immunization; In Vitro; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modeling; Monitor; Mus; Natural Killer Cells; Nature; Outcome Study; Patients; Phenotype; Population; Property; Protein Family; Protocols documentation; Radiation Tolerance; Recovery; Recurrence; Residual Tumors; Residual state; Role; Sampling; Sequential Treatment; Series; Site; Stable Disease; Stains; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Treatment Protocols; Tumor Immunity; Tumor-infiltrating immune cells; Work; Xenograft procedure; anti-tumor immune response; assault; base; cancer recurrence; cell growth; chemotherapy; defined contribution; design; drug sensitivity; experimental study; immunogenic; immunogenic cell death; in vitro Model; in vivo; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; pre-clinical; preclinical study; prevent; response; self-renewal; senescence; therapeutic effectiveness; translational goal; treatment response; tumor

Abstract/Summary Chemotherapy and radiation can induce breast tumors to enter a prolonged state of growth arrest with characteristics of senescence. A senescent-like state is also characteristic of residual tumor cells that survive after chemotherapy and/or radiation have eliminated the bulk of a tumor cell population. Tumor cells surviving therapy-induced senescence have the capacity to recover proliferative capacity subsequent to their prolonged growth arrest. Recovery and re-emergence of tumor cells from this growth-arrested state could contribute to disease recurrence months or years after the patient has apparently been cured of the primary disease. Several agents have recently been identified as having senolytic properties [e.g. ABT-263 (navitoclax)] which can selectively kill senescent cells. Given that disease recurrence and consequent cancer mortality is frequently associated with the re-emergence of proliferative tumor cells either at the primary disease site or metastatic sites, a primary goal of this project will be to test the hypothesis that senolytic agents can eliminate therapy induced senescent breast tumor cells to prevent, or at least significantly suppress, cancer recurrence. Aim 1 will examine the hypothesis that the senolytic agent, ABT-263, can efficiently eliminate cells induced into senescence by chemotherapy or radiation when used sequentially (and potentially, repeatedly) after the initial therapy. Sensitivity to senolytics will be assessed in senescence-sorted breast tumor cells, prior to senescence and during the course of recovery, and in residual populations surviving after the bulk of the tumor population has been eliminated by therapeutic agents. The effectiveness of a sequential treatment schedule will also be assessed in vivo using xenograft and PDX tumor models. Aim 2 will interrogate the mechanisms whereby the senolytic ABT-263 promotes cell death in senescent breast tumor cells, with a focus on the contributions of pro- and anti-apoptotic BCL-2 family proteins. Aim 3 will examine the immune response to therapy-induced senescent cells alone and after treatment with senolytics. A phenotypic assessment of tumor infiltrating immune cells and studies with selective immune cell depletion in mouse models will define the nature (adaptive and innate) of the antitumor immune response. Ex vivo studies will further determine NK- and T cell-mediated lysis of senescent cells in the absence or presence of ABT-263. The ability of senolytics to induce immunogenic cell death will be a focus. Toxicity to the host will be compared for exposure to senolytics concomitant with chemotherapy (i.e. prior to entry into senescence) and subsequent to induction of senescence.

摘要/总结 化疗和放疗可诱导乳腺肿瘤进入长时间的生长停滞状态 衰老的特征。类衰老状态也是存活的残留肿瘤细胞的特征 化疗和/或放疗消除了大部分肿瘤细胞群后。肿瘤细胞存活 治疗引起的衰老在延长寿命后能够恢复增殖能力 生长停滞。肿瘤细胞从这种生长停滞状态中恢复和重新出现可能有助于 患者原发疾病明显治愈数月或数年后疾病复发。 最近已确定几种药物具有抗衰老特性 [例如ABT-263（navitoclax）] 可以选择性地杀死衰老细胞。鉴于疾病复发和随之而来的癌症死亡率 通常与原发病部位或原发部位增殖性肿瘤细胞的重新出现有关 转移位点，该项目的主要目标是测试 senolytic 药物可以消除转移位点的假设 疗法诱导衰老的乳腺肿瘤细胞以预防或至少显着抑制癌症复发。 目标 1 将检验衰老抑制剂 ABT-263 可以有效消除细胞的假设 当连续（并且可能重复）使用化疗或放疗后，会诱导衰老 初始治疗。在衰老分选的乳腺肿瘤细胞中，将评估对衰老药物的敏感性。 衰老和恢复过程中，以及在肿瘤体积增大后幸存的残余群体中 人群已被治疗剂消灭。序贯治疗计划的有效性将 也可以使用异种移植和 PDX 肿瘤模型进行体内评估。 目标 2 将探究 senolytic ABT-263 促进衰老细胞死亡的机制 乳腺肿瘤细胞，重点关注促凋亡和抗凋亡 BCL-2 家族蛋白的贡献。 目标 3 将检查单独和治疗后对治疗诱导的衰老细胞的免疫反应 与 senolytics 一起使用。肿瘤浸润免疫细胞的表型评估和选择性免疫研究 小鼠模型中的细胞耗竭将定义抗肿瘤免疫反应的性质（适应性和先天性）。 离体研究将进一步确定 NK 和 T 细胞介导的衰老细胞在不存在或存在的情况下的裂解 ABT-263。 senolytics 诱导免疫原性细胞死亡的能力将成为焦点。对宿主有毒性 比较化疗期间（即进入衰老之前）与 senolytics 的接触情况 诱导衰老后。