Enhancing triple negative breast cancer response to immune checkpoint inhibitor therapy via targeted therapies

通过靶向治疗增强三阴性乳腺癌对免疫检查点抑制剂治疗的反应

• 批准号: 10607065
• 负责人: Kennady Bullock
• 金额: $ 3.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607065
• 关键词: 4T1; AKT inhibition; Affect; Blood; Breast Cancer Cell; Breast Cancer Patient; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Clinic; Clinical; Clinical Trials; Coculture Techniques; Collaborations; Color; Combined Modality Therapy; Data; Data Set; Development; Disease; Distant; EO771; Environment; Excision; Exhibits; FDA approved; Failure; Flow Cytometry; Gene Expression Profiling; Genetic; Genomics; Goals; Growth; Immune; Immune checkpoint inhibitor; Immunophenotyping; Immunotherapy; In Vitro; Lymphoid Cell; Maintenance; Mediating; Modeling; Mus; Myeloid Cells; Operative Surgical Procedures; Organoids; PI3K/AKT; PIK3CG gene; Paclitaxel; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Population; Pre-Clinical Model; Property; Proteomics; Proto-Oncogene Proteins c-akt; Recurrence; Resistance; Role; Signal Pathway; Site; Spleen; Survival Rate; System; T-Lymphocyte; Testing; Therapeutic Effect; Toxic effect; Treatment Efficacy; Tumor-infiltrating immune cells; Unresectable; Up-Regulation; Work; anti-CTLA4; anti-PD-1; anti-PD-L1; anti-PD1 therapy; anti-cancer; candidate identification; cell killing; checkpoint inhibition; checkpoint therapy; chemotherapy; drug candidate; experimental study; high throughput screening; human model; immune activation; in vivo; inhibitor; lymph nodes; malignant breast neoplasm; melanoma; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; phosphoproteomics; polyoma middle tumor antigen; preclinical development; predicting response; recruit; resistance mechanism; response; standard of care; synergism; targeted treatment; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor-immune system interactions

Project Summary Triple negative breast cancer (TNBC) is a subtype of breast cancer that is aggressive and difficult to treat, with limited treatment options beyond traditional chemotherapy. Given the recent approval of treatment of TNBC with the immune checkpoint inhibitors, anti-PD1 and anti-PDL1, combined with nab-paclitaxel, we are evaluating strategies that prime tumors to be more responsive to immune checkpoint inhibitors (ICI). Overactivation of the PI3K/AKT pathway is implicated in about 23.7% of TNBC tumors and is known to contribute to the maintenance of an immunosuppressive tumor immune microenvironment (TIME). This proposal will investigate the hypothesis that pan-AKT inhibition (AKTi) will enhance the efficacy of treatment with existing immune checkpoint inhibitors in some but not all preclinical models of TNBC, including mouse models and patient-derived organoid models. Experiments proposed in aim 1 will investigate how pan-AKTi affects the TIME when used in conjunction with anti-PD-1, anti-CTLA4, and a combination of anti-PD-1 + anti-CTLA4 (ICI). In vivo murine studies will be performed in AKTi responsive PYMT tumors and AKTi non-responsive EO771, 4T1, and 6DT1 tumors. Multi- color flow cytometry will allow detailed immunophenotyping of tumor and peripheral sites such as blood,lymph node, and spleen. Additionally, In vitro studies with T-cells will explore the mechanisms through which AKTi may enhance ICI efficacy as well as mechanisms of resistance to AKTi. In aim 2, a high throughput screen will be used to identify potential candidate drugs that enhance T cell-mediated tumor cell killing and therefore have the potential to enhance the efficacy of existing immune checkpoint inhibitors. A number of pan-AKT inhibitors as well as candidate drugs identified in the screen will be evaluated in patient-derived organoid models established from TNBC patients undergoing surgical resection. We will look for synergism between AKTi with immune checkpoint inhibition, evaluating direct AKTi-mediated tumor cell killing and immune-mediated tumor cell killing. These studies will enhance our understanding of mechanisms of response and resistance to AKTi in TNBC and the role of AKT inhibition in priming the tumor immune environment to enhance response to immune checkpoint inhibitors. We will identify alternative inhibitors that enhance TNBC response to ICI for those tumors that do not respond to AKTi. By examining the response of these therapies in organoid models of human TNBC, we will be able to predict parameters of response to therapy in a heterogenous population of TNBC patients.

项目摘要 三阴性乳腺癌(TNBC)是乳腺癌的一种亚型，具有侵袭性，难以治疗。 传统化疗以外的治疗选择有限。鉴于最近批准对TNBC的治疗 免疫检查点抑制剂，抗PD1和抗PDL1，与NaB-紫杉醇联合使用，我们正在评估 启动肿瘤对免疫检查点抑制剂(ICI)更敏感的策略。过度激活 PI3K/AKT通路与大约23.7%的TNBC肿瘤有关，并被认为与肿瘤的维持有关 免疫抑制肿瘤免疫微环境(TIME)。这项提案将调查这一假说 PAN-AKT抑制(Akti)将增强现有免疫检查点抑制剂的治疗效果 在一些但不是所有的TNBC临床前模型中，包括小鼠模型和患者衍生的器官模型。 目标1中提出的实验将调查PAN-AKTI在与 抗PD-1、抗CTLA4和抗PD-1+抗CTLA4(ICI)的组合。在体内的小鼠研究将是 在Akti反应性PYMT肿瘤和Akti无反应性EO771、4T1和6DT1肿瘤中进行。多个- 彩色流式细胞术将允许对肿瘤及其周围部位(如血液、淋巴)进行详细的免疫表型分析 结节和脾。此外，T细胞的体外研究将探索Akti可能通过的机制 增强ICI的疗效以及对Akti的耐药机制。在AIM 2中，高通量屏幕将是 用于识别潜在的候选药物，这些药物可以增强T细胞介导的肿瘤细胞杀伤，因此具有 有可能提高现有免疫检查点抑制剂的疗效。一些PAN-AKT抑制剂，如 以及在筛选中确定的候选药物将在建立的患者衍生有机物模型中进行评估 来自接受手术切除的TNBC患者。我们将寻找Akti与免疫之间的协同效应 检查点抑制，评价Akti介导的直接肿瘤细胞杀伤和免疫介导的肿瘤细胞杀伤。 这些研究将加深我们对TNBC和TBC对Akti的反应和耐药机制的理解 AKT抑制在启动肿瘤免疫环境增强免疫检查点应答中的作用 抑制剂。我们将为那些不起作用的肿瘤寻找增强TNBC对ICI反应的替代抑制剂 回复阿克蒂。通过检查这些疗法在人类TNBC器官模型中的反应，我们将 能够预测不同类型的TNBC患者的治疗反应参数。