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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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要三阴性乳腺癌（TNBC）是乳腺癌的一种亚型，具有侵袭性且难以治疗，除了传统化疗之外，治疗选择有限。鉴于最近批准了 TNBC 治疗免疫检查点抑制剂抗PD1和抗PDL1与白蛋白结合型紫杉醇联合使用，我们正在评估使肿瘤对免疫检查点抑制剂（ICI）更加敏感的策略。过度激活 PI3K/AKT 通路与约 23.7% 的 TNBC 肿瘤有关，已知有助于维持免疫抑制性肿瘤免疫微环境（TIME）。该提案将调查假设泛 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 TNBC 临床前模型中，包括小鼠模型和患者来源的类器官模型。目标 1 中提出的实验将研究 pan-AKTi 与以下命令结合使用时如何影响 TIME：抗 PD-1、抗 CTLA4 以及抗 PD-1 + 抗 CTLA4 的组合 (ICI)。小鼠体内研究将在 AKTi 反应性 PYMT 肿瘤和 AKTi 无反应性 EO771、4T1 和 6DT1 肿瘤中进行。多- 彩色流式细胞术将允许对肿瘤和外周部位（例如血液、淋巴）进行详细的免疫表型分析节点和脾脏。此外，T 细胞体外研究将探索 AKTi 可能的机制增强 ICI 功效以及 AKTi 耐药机制。在目标 2 中，将采用高通量筛选用于识别增强 T 细胞介导的肿瘤细胞杀伤作用的潜在候选药物，因此具有增强现有免疫检查点抑制剂功效的潜力。许多泛 AKT 抑制剂以及筛选中确定的候选药物将在建立的源自患者的类器官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伤。这些研究将增强我们对 TNBC 和 AKTi 反应和耐药机制的理解 AKT 抑制在启动肿瘤免疫环境以增强对免疫检查点的反应中的作用抑制剂。我们将寻找替代抑制剂，增强 TNBC 对 ICI 的反应，以治疗那些不能治疗的肿瘤。响应 AKTi。通过检查这些疗法在人类 TNBC 类器官模型中的反应，我们将能够预测异质 TNBC 患者群体的治疗反应参数。