Project 3: Hedgehog Inhibition to Enhance Response to ICI Therapy
Project 3: Hedgehog Inhibition to Enhance Response to ICI Therapy
批准号:
10713054
负责人:
Ronald J Buckanovich
金额:
$37.2万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-01 至 2028-08-31
关键词:
BindingBiological Response ModifiersBiopsyBloodCD8-Positive T-LymphocytesCXCL9 geneCancer PatientCarcinomaCellsClinical TrialsCorrelative StudyDataDoseEffector CellErinaceidaeEventExclusionFibroblastsFosteringHumanImmuneImmune checkpoint inhibitorImmunosuppressionImmunotherapeutic agentIn VitroInfiltrationLeadLinkMacrophageMalignant neoplasm of ovaryMeasuresMediatingMediatorMesenchymal Stem CellsModelingMusMyeloid CellsNatural Killer CellsOvarian CarcinomaPatient-Focused OutcomesPatientsPeripheralPeripheral Blood Mononuclear CellPhasePhase II Clinical TrialsPhenotypePhysiologic pulsePlasmaPlatinumPrediction of Response to TherapyProgression-Free SurvivalsProteinsRecurrenceReportingResistanceRoleSafetyT cell receptor repertoire sequencingT cell regulationT-Cell ActivationT-LymphocyteTGFBI geneTestingTissuesTransforming Growth Factor betaTumor ImmunityTumor TissueTumor-associated macrophagesTumor-infiltrating immune cellsanti-PD-L1armcancer cellcell motilitycheckpoint therapychemokinecytokinedesigngenetic approachhumanized mouseimmune cell infiltrateimproved outcomein vivoinhibitorinhibitor therapyisletmigrationmonocytemouse modelnano-stringneutralizing antibodynew therapeutic targetpatient prognosispatient responsepreclinical studypredicting responsepredictive markerprimary endpointrecruitresponserestorationsecondary endpointsingle-cell RNA sequencingsmoothened signaling pathwaytherapeutic targettherapy outcometranslational studytreatment responsetumortumor microenvironmenttumor-immune system interactions
中文摘要
摘要/摘要-项目3
英文摘要
SUMMARY/ABSTRACT – PROJECT 3
When effective, immune checkpoint inhibitor (ICI) therapy can significantly improve the outcome of patients with
ovarian cancer (OvCa). However, only 10-20% of OvCa patients respond to ICI therapy. One reason for the low
ICI response rate of OvCa may be OvCa’s unique immunosuppressive tumor microenvironment (TME), which is
typified by a dense stroma infiltrated by immunosuppressive ‘M2’ tumor associated macrophages (TAMs). We
recently found that ovarian carcinoma-associated mesenchymal stem cells (CA-MSC) orchestrate an
immunosuppressive OvCa TME; differentiating into BIGH3 expressing fibroblast/tumor stroma, recruiting
monocytes to the stroma, and promoting the differentiation of immunosuppressive BIGH3 expressing ‘M2’ TAMs.
The combined effect is that CA-MSC drive tumor immune exclusion and a resultant resistance to ICI
therapy. Importantly, we find that hedgehog inhibitors (HHi) reverse CA-MSC-driven immune exclusion,
promote M2 to M1 TAM conversion, and restore response to ICI therapy. HHi therapy down-regulates
BIGH3 in CA-MSC and TAMs, and promotes the conversion of TAMs from an M2 to and M1 phenotype. Our
studies are consistent with numerous recent reports that HHi promote M1 macrophage polarization and promote
anti-tumor immunity. Based on these results, we hypothesize that CA-MSC create an immunosuppressive OvCa
TME and that HHi will reverse CA-MSC mediated immune-suppression and enhance patient response to ICI
therapy. To test our hypothesis, we propose the following specific aims: SA1. Conduct a single arm Phase-II
clinical trial evaluating Atezolizumab (aPD-L1) combined with Vismodegib (HHi) in patients with platinum
resistant recurrent ovarian cancer. Primary endpoints will be efficacy and safety. Secondary endpoints will be
duration of response, PFS, OS and translational correlatives. SA2: Evaluate the impact of HHi on patients’
tumor immune infiltrates and peripheral chemokines and determine if changes predict response to therapy.
SA3: To assess BIGH3 as a driver of tumor immune exclusion and immunotherapeutic target. Using
murine models of OvCa, we will assess the impact of BIGH3 on immune effector migration and function and
determine if anti-BIGH3 therapy can enhance ICI response in murine tumor models.
IMPACT: This will be the first clinical trial in OvCa to determine (i) the impact of HHi on ICI therapy in patients
with epithelial cancer, and (ii) the role of targeting CA-MSCs to overcome the immunosuppressive OvCa TME.
Correlative translational studies will reveal potential predictive biomarkers of response to therapy. Finally, we
will evaluate BIGH3 as an immune regulator and novel therapeutic target. Ultimately, we believe these studies
will impact OvCa patient’s response to ICI therapy and will improve outcomes.
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会议论文
Administrative Core
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批准号:10713051
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项目类别:
-
资助金额:$23.49万
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财政年份:2023
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负责人:Ronald J Buckanovich
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依托单位:
HCC Ovarian Cancer SPORE
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批准号:10713050
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项目类别:
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资助金额:$216.38万
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财政年份:2023
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负责人:Ronald J Buckanovich
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依托单位:
Evaluating unique aspects of quiescent ovarian cancer cell biology for therapeutic targets
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批准号:10750118
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项目类别:
-
资助金额:$43.81万
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财政年份:2023
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负责人:Ronald J Buckanovich
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依托单位:
Defining the impact of stromal aging on ovarian cancer initiation
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批准号:10353485
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项目类别:
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资助金额:$46.64万
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财政年份:2021
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负责人:Ronald J Buckanovich
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依托单位:
Defining the impact of stromal aging on ovarian cancer initiation
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批准号:10491889
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项目类别:
-
资助金额:$45.76万
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财政年份:2021
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负责人:Ronald J Buckanovich
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依托单位:
Defining the impact of stromal aging on ovarian cancer initiation
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批准号:10659225
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项目类别:
-
资助金额:$45.81万
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财政年份:2021
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负责人:Ronald J Buckanovich
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依托单位:
ALDH Inhibition as Modulator of Tumor Immunobiology
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批准号:10392913
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项目类别:
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资助金额:$43.18万
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财政年份:2020
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负责人:Ronald J Buckanovich
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依托单位:
ALDH Inhibition as Modulator of Tumor Immunobiology
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批准号:10380368
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项目类别:
-
资助金额:$6.04万
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财政年份:2020
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负责人:Ronald J Buckanovich
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依托单位:
ALDH Inhibition as Modulator of Tumor Immunobiology
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批准号:10524133
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项目类别:
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资助金额:$1.45万
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财政年份:2020
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负责人:Ronald J Buckanovich
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依托单位:
ALDH Inhibition as Modulator of Tumor Immunobiology
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批准号:10649413
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项目类别:
-
资助金额:$42.77万
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财政年份:2020
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负责人:Ronald J Buckanovich
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依托单位:
The Function of EGFL6 in Ovarian Cancer Cell Biology, Tumor Initiation, and Therapy
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批准号:10304184
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项目类别:
-
资助金额:$33.67万
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财政年份:2018
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负责人:Ronald J Buckanovich
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依托单位:
The Function of EGFL6 in Ovarian Cancer Cell Biology, Tumor Initiation, and Therapy
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批准号:10061581
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项目类别:
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资助金额:$34.35万
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财政年份:2018
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负责人:Ronald J Buckanovich
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依托单位:
The Function of EGFL6 in Ovarian Cancer Cell Biology, Tumor Initiation, and Therapy
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批准号:10533768
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项目类别:
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资助金额:$33.67万
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财政年份:2018
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负责人:Ronald J Buckanovich
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依托单位:
Using microfluidic single cell culture to characterize cancer cell asymmetric division
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批准号:9237393
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项目类别:
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资助金额:$43.31万
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财政年份:2017
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负责人:Ronald J Buckanovich
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依托单位:
Isozyme-selective ALDH Inhibitors for Sensitizing Ovarian Cancer Stem-like Cells to Chemotherapy
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批准号:9288503
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项目类别:
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资助金额:$63.62万
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财政年份:2017
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负责人:Ronald J Buckanovich
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依托单位:
Developing a Human in Mouse Cancer Model with a Completely Humanized Stroma
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批准号:10246576
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项目类别:
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资助金额:$8.0万
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财政年份:2017
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负责人:Ronald J Buckanovich
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依托单位:
Training in Cancer Therapeutics Research
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批准号:9753159
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项目类别:
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资助金额:$8.82万
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财政年份:2015
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负责人:Ronald J Buckanovich
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依托单位:
Targeting Ovarian Tumor Associated Myeloid Cells with Nanoparticles Therapeutics
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批准号:9012021
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项目类别:
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资助金额:$32.27万
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财政年份:2012
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负责人:Ronald J Buckanovich
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依托单位:
Targeting Ovarian Tumor Associated Myeloid Cells with Nanoparticles Therapeutics
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批准号:8619516
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项目类别:
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资助金额:$31.3万
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财政年份:2012
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负责人:Ronald J Buckanovich
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依托单位:
Targeting Ovarian Tumor Associated Myeloid Cells with Nanoparticles Therapeutics
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批准号:8434838
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项目类别:
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资助金额:$30.33万
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财政年份:2012
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负责人:Ronald J Buckanovich
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依托单位:
海外基金