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:
- 金额:$ 3.3万
- 依托单位:
- 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:
- 关键词:4T1AKT inhibitionAffectBloodBreast Cancer CellBreast Cancer PatientCD8-Positive T-LymphocytesCell physiologyCellsClinicClinicalClinical TrialsCoculture TechniquesCollaborationsColorCombined Modality TherapyDataData SetDevelopmentDiseaseDistantEO771EnvironmentExcisionExhibitsFDA approvedFailureFlow CytometryGene Expression ProfilingGeneticGenomicsGoalsGrowthImmuneImmune checkpoint inhibitorImmunophenotypingImmunotherapyIn VitroLymphoid CellMaintenanceMediatingModelingMusMyeloid CellsOperative Surgical ProceduresOrganoidsPI3K/AKTPIK3CG genePaclitaxelPathway interactionsPatientsPeripheralPharmaceutical PreparationsPhenotypePhosphotransferasesPopulationPre-Clinical ModelPropertyProteomicsProto-Oncogene Proteins c-aktRecurrenceResistanceRoleSignal PathwaySiteSpleenSurvival RateSystemT-LymphocyteTestingTherapeutic EffectToxic effectTreatment EfficacyTumor-infiltrating immune cellsUnresectableUp-RegulationWorkanti-CTLA4anti-PD-1anti-PD-L1anti-PD1 therapyanti-cancercandidate identificationcell killingcheckpoint inhibitioncheckpoint therapychemotherapydrug candidateexperimental studyhigh throughput screeninghuman modelimmune activationin vivoinhibitorlymph nodesmalignant breast neoplasmmelanomamouse modelneoplastic cellnew therapeutic targetnovelnovel therapeuticsphosphoproteomicspolyoma middle tumor antigenpreclinical developmentpredicting responserecruitresistance mechanismresponsestandard of caresynergismtargeted treatmenttreatment responsetriple-negative invasive breast carcinomatumortumor growthtumor-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
用于识别增强T细胞介导的肿瘤细胞杀伤的潜在候选药物,因此具有
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。
项目成果
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