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 三重阴性乳腺癌（TNBC）是乳腺癌的亚型，具有侵略性且难以治疗的乳腺癌 传统化学疗法以外的有限治疗选择。鉴于最近批准了TNBC的治疗 免疫检查点抑制剂抗PD1和抗PDL1与NAB-PACLITAXEL相结合，我们正在评估 对免疫检查点抑制剂（ICI）更敏感的主要肿瘤的策略。过度活化 PI3K/AKT途径与大约23.7％的TNBC肿瘤有关，已知有助于维护 免疫抑制性肿瘤免疫微环境（时间）。该提议将调查假设 Pan-Akt抑制（AKTI）将增强使用现有免疫检查点抑制剂治疗的功效 在某些但不是所有TNBC的临床前模型中，包括小鼠模型和患者衍生的类器官模型。 AIM 1中提出的实验将研究Pan-Akti如何影响与 抗PD-1，抗CTLA4和抗PD-1 +抗CTLA4（ICI）的组合。体内鼠研究将是 在AKTI反应性PYMT肿瘤和AKTI非反应性EO771、4T1和6DT1肿瘤中进行。多- 颜色流式细胞术将允许肿瘤和外周部位的详细免疫表型，例如血液，淋巴 节点和脾脏。此外，对T细胞的体外研究将探索Akti可以通过的机制 提高ICI功效以及对Akti的抗性机制。在AIM 2中，高吞吐量屏幕将是 用于识别增强T细胞介导的肿瘤细胞杀死的潜在候选药物，因此 增强现有免疫检查点抑制剂功效的潜力。许多pan-akt抑制剂 以及在屏幕上确定的候选药物将在建立的患者衍生器官模型中评估 来自接受手术切除的TNBC患者。我们将寻找免疫力的Akti之间的协同作用 检查点抑制，评估直接AKTI介导的肿瘤细胞杀伤和免疫介导的肿瘤细胞杀死。 这些研究将增强我们对TNBC和对Akti反应机制的理解和TNBC和 AKT抑制在启动肿瘤免疫环境中增强对免疫检查点的反应的作用 抑制剂。我们将确定替代抑制剂，这些抑制剂可增强TNBC对ICI的反应 回应Akti。通过检查这些疗法在人类TNBC的器官模型中的反应，我们将是 能够预测TNBC患者异源群体中对治疗反应的参数。