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: 10581513
• 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/10581513
• 关键词: Aftercare; Animals; Antigens; Antitumor Response; Apoptotic; BCL1 Oncogene; BCL2L1 gene; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Characteristics; Chemotherapy and/or radiation; Clinic; Clinical Trials; Cross Presentation; Cytolysis; Data; Disease; Dose; Effectiveness; Experimental Designs; Exposure to; Goals; Growth; Human; Immune; Immune response; Immune system; Immunologic Stimulation; In Vitro; Induction of Apoptosis; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modeling; Monitor; Mus; Natural Killer Cells; Nature; Outcome Study; Patients; Phenotype; Population; Property; Protein Family; Protocols documentation; Radiation; Radiation Tolerance; Recovery; Recurrent Malignant Neoplasm; Recurrent disease; Residual Neoplasm; Residual state; Role; Sampling; Sequential Treatment; Series; Site; Sorting; 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; 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/概要 化疗和放疗可以诱导乳腺肿瘤进入长时间的生长停滞状态， 衰老的特征。衰老样状态也是残存肿瘤细胞存活的特征 在化疗和/或放疗已经消除了大部分肿瘤细胞群体之后。肿瘤细胞存活 治疗诱导的衰老有能力恢复增殖能力， 生长停滞肿瘤细胞从这种生长停滞状态的恢复和重新出现可能有助于 在患者的原发病明显治愈后数月或数年内疾病复发。 几种药物最近被鉴定为具有衰老清除特性[例如ABT-263（navitoclax）] 可以选择性杀死衰老细胞。考虑到疾病复发和随之而来的癌症死亡率， 通常与原发性疾病部位的增殖性肿瘤细胞重新出现有关， 转移部位，该项目的主要目标将是测试假设，senolytic剂可以消除 治疗诱导衰老的乳腺肿瘤细胞，以防止或至少显著抑制癌症复发。 目的1将检验衰老清除剂ABT-263可以有效清除细胞的假设 当化疗或放疗后连续使用（可能反复使用）时， 最初的治疗。将在衰老分选的乳腺肿瘤细胞中评估对衰老溶解剂的敏感性， 衰老和在恢复过程中，以及在大部分肿瘤后存活的残余群体中， 人口已被消除的治疗剂。序贯治疗方案的有效性将 还使用异种移植物和PDX肿瘤模型在体内评估。 目的2将探讨衰老清除剂ABT-263促进衰老细胞死亡的机制， 乳腺肿瘤细胞，重点是促凋亡和抗凋亡BCL-2家族蛋白的贡献。 目的3将检查单独和治疗后对治疗诱导的衰老细胞的免疫应答 关于Senolytics肿瘤浸润性免疫细胞的表型评估和选择性免疫的研究 小鼠模型中的细胞耗竭将确定抗肿瘤免疫应答的性质（适应性和先天性）。 离体研究将进一步确定NK细胞和T细胞介导的衰老细胞裂解， ABT-263 senolytics诱导免疫原性细胞死亡的能力将是一个焦点。对宿主的毒性 比较与化疗同时暴露于抗衰老药物（即进入衰老之前），以及 随后诱导衰老。