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.
项目总结
项目成果
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