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)是乳腺癌的一种亚型,具有侵袭性,难以治疗。
传统化疗以外的治疗选择有限。鉴于最近批准对TNBC的治疗
免疫检查点抑制剂,抗PD1和抗PDL1,与NaB-紫杉醇联合使用,我们正在评估
启动肿瘤对免疫检查点抑制剂(ICI)更敏感的策略。过度激活
PI3K/AKT通路与大约23.7%的TNBC肿瘤有关,并被认为与肿瘤的维持有关
免疫抑制肿瘤免疫微环境(TIME)。这项提案将调查这一假说
PAN-AKT抑制(Akti)将增强现有免疫检查点抑制剂的治疗效果
在一些但不是所有的TNBC临床前模型中,包括小鼠模型和患者衍生的器官模型。
目标1中提出的实验将调查PAN-AKTI在与
抗PD-1、抗CTLA4和抗PD-1+抗CTLA4(ICI)的组合。在体内的小鼠研究将是
在Akti反应性PYMT肿瘤和Akti无反应性EO771、4T1和6DT1肿瘤中进行。多个-
彩色流式细胞术将允许对肿瘤及其周围部位(如血液、淋巴)进行详细的免疫表型分析
结节和脾。此外,T细胞的体外研究将探索Akti可能通过的机制
增强ICI的疗效以及对Akti的耐药机制。在AIM 2中,高通量屏幕将是
用于识别潜在的候选药物,这些药物可以增强T细胞介导的肿瘤细胞杀伤,因此具有
有可能提高现有免疫检查点抑制剂的疗效。一些PAN-AKT抑制剂,如
以及在筛选中确定的候选药物将在建立的患者衍生有机物模型中进行评估
来自接受手术切除的TNBC患者。我们将寻找Akti与免疫之间的协同效应
检查点抑制,评价Akti介导的直接肿瘤细胞杀伤和免疫介导的肿瘤细胞杀伤。
这些研究将加深我们对TNBC和TBC对Akti的反应和耐药机制的理解
AKT抑制在启动肿瘤免疫环境增强免疫检查点应答中的作用
抑制剂。我们将为那些不起作用的肿瘤寻找增强TNBC对ICI反应的替代抑制剂
回复阿克蒂。通过检查这些疗法在人类TNBC器官模型中的反应,我们将
能够预测不同类型的TNBC患者的治疗反应参数。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Kennady Bullock其他文献
Kennady Bullock的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
Elucidating resistance to AKT inhibition in metastatic breast cancer
阐明转移性乳腺癌对 AKT 抑制的耐药性
- 批准号:
2440937 - 财政年份:2020
- 资助金额:
$ 3.3万 - 项目类别:
Studentship
The Risk of Novel AKT Inhibition on Lethal Neuroendocrine Prostate Cancer Development
新型 AKT 抑制对致死性神经内分泌前列腺癌发展的风险
- 批准号:
350042 - 财政年份:2015
- 资助金额:
$ 3.3万 - 项目类别:
Studentship Programs
Mechanistic studies of cancer cell adaptive response to PI3K/AKT inhibition
癌细胞对 PI3K/AKT 抑制的适应性反应的机制研究
- 批准号:
9272854 - 财政年份:2015
- 资助金额:
$ 3.3万 - 项目类别:
Targeting RAS signaling with CDK and AKT inhibition in pancreatic cancer
通过 CDK 和 AKT 抑制作用靶向胰腺癌中的 RAS 信号传导
- 批准号:
8581465 - 财政年份:2013
- 资助金额:
$ 3.3万 - 项目类别:
Targeting RAS signaling with CDK and AKT inhibition in pancreatic cancer
通过 CDK 和 AKT 抑制作用靶向胰腺癌中的 RAS 信号传导
- 批准号:
8692694 - 财政年份:2013
- 资助金额:
$ 3.3万 - 项目类别: