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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.

项目摘要三阴性乳腺癌（TNBC）是一种侵袭性且难以治疗的乳腺癌亚型，传统化疗以外的治疗选择有限。考虑到最近批准的TNBC的治疗，免疫检查点抑制剂，抗PD 1和抗PDL 1，与白蛋白结合型紫杉醇，我们正在评估这些策略使肿瘤对免疫检查点抑制剂（ICI）更具反应性。过度激活 PI 3 K/AKT途径与约23.7%的TNBC肿瘤有关，并且已知有助于维持肿瘤免疫微环境（TIME）这份提案将调查这一假设泛AKT抑制（AKTi）将增强现有免疫检查点抑制剂的治疗效果在TNBC的一些但非所有临床前模型中，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当与以下结合使用时，泛AKTi如何影响TIME 抗PD-1、抗CTLA 4和抗PD-1 +抗CTLA 4（ICI）的组合。将进行体内鼠研究。在AKTi响应性PYMT肿瘤和AKTi非响应性E0 771、4 T1和6DT 1肿瘤中进行。多重彩色流式细胞术将允许肿瘤和外周部位如血液、淋巴淋巴结和脾脏。此外，T细胞的体外研究将探索AKTi可能增强ICI功效以及对AKTi的抗性机制。在目标2中，高通量筛选将是用于鉴定增强T细胞介导的肿瘤细胞杀伤的潜在候选药物，有可能增强现有免疫检查点抑制剂的功效。许多泛AKT抑制剂，以及筛选中确定的候选药物将在建立的患者来源的类器官模型中进行评估接受手术切除的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中对AKTi的响应和抗性机制的理解， AKT抑制在启动肿瘤免疫环境以增强对免疫检查点的应答中的作用抑制剂的我们将确定替代抑制剂，增强TNBC对ICI的反应，用于那些不能增强TNBC对ICI反应的肿瘤。回复AKTi通过检查这些疗法在人TNBC的类器官模型中的反应，我们将研究这些疗法在人TNBC的类器官模型中的作用。能够预测TNBC患者的异质群体中对治疗的响应的参数。