Novel Therapeutic Approaches for Aggressive Prostate Cancer
侵袭性前列腺癌的新治疗方法
基本信息
- 批准号:10734381
- 负责人:
- 金额:$ 38.32万
- 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 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdenocarcinomaAggressive behaviorBindingCellsChemoresistanceClinicClinical TrialsCoupledDataGoalsImmuneImmune EvasionImmune checkpoint inhibitorImmune responseImmunocompetentImmunosuppressionInvadedMalignant NeoplasmsMalignant neoplasm of prostateMediatingMetastatic Prostate CancerModelingMonoclonal AntibodiesMorbidity - disease rateMusNPR2 geneNeoplasm MetastasisNeuroendocrine Prostate CancerNeuroendocrine TherapyNeuropilin-2OutcomePhenotypePredispositionPropertyReportingResistanceRoleSignal TransductionTherapeuticToxic effectTumor BurdenTumor ImmunityTumor PromotionUp-RegulationVascular Endothelial Growth FactorsWorkadvanced prostate cancerautocrinecell killingcheckpoint inhibitionchemotherapyeffective therapyexosomehumanized antibodyimprovedinhibitormanufacturemortalityneoplastic cellnonhuman primatenovelnovel therapeutic interventionpressureprogrammed cell death ligand 1programmed cell death protein 1prostate cancer modelreceptorresponsestem cellsstemnesstherapeutic targettranslational potentialtreatment strategytumortumor progression
项目摘要
Summary
The goal of this proposal is to develop a novel therapeutic strategy for the treatment of neuroendocrine
prostate cancer (NEPC) that has the potential for translation to the clinic. NEPC is an aggressive form of
prostate cancer that is associated with rapid progression, resistance to treatments and a very poor outcome.
Currently, there are no effective therapies for treating NEPC. This revised proposal focuses on the hypothesis
that programmed cell death 1 ligand (PD-L1) has a causal role in the stemness and metastatic propensity
associated with NEPC. Although PD-L1 is best known for its role in immune suppression, its tumor cell
intrinsic functions that are independent of immune suppression can also contribute to cancer progression.
Specifically, PD-L1 has been implicated in tumor stemness, invasion and metastasis and there is
circumstantial evidence that it contributes to these functions in NEPC, although a causal role has yet to be
demonstrated. This novel function of PD-L1 can be exploited to improve the therapy of NEPC based on
compelling evidence that VEGF/NRP2 signaling sustains the expression of PD-L1 in prostate cancer.
Inhibiting VEGF/NRP2 reduces stem cell properties and promotes a more differentiated phenotype that is more
susceptible to chemotherapy, and it is likely that the mechanism involves reducing PD-L1 expression. Also, a
humanized mAb is available that inhibits the binding of VEGF to NRP2. This mAb does not cause toxicity in
mice and non-human primates and is being manufactured for use in clinical trials. Of note, this mAb diminishes
the expression of PD-L1 significantly in models of NEPC. Together, these observations formulate a central
hypothesis: PD-L1 has a causal role in NEPC by sustaining stemness and facilitating metastasis (cell
autonomous PD-L1 function) and by promoting immune cell evasion (non-cell autonomous PD-L1 function).
Both critical functions of PD-L1 can be blocked by therapeutic targeting of VEGF binding to NRP2 to improve
the morbidity and mortality associated with NEPC. The first specific aim will investigate a therapeutic strategy
for inhibiting tumor cell intrinsic functions of PD-L1 to mitigate stemness and metastasis in NEPC that involves
blocking the binding of VEGF to NRP2. The second aim will investigate therapeutic strategies that target PD-
1-dependent and PD-1-independent functions of PD-L1 in NEPC by blocking the binding of VEGF to NPR2
using immune competent models. The data generated in this proposal have the potential to provide sufficient
evidence to justify the initiation of clinical trials using NRP2 inhibitors, especially the function-blocking Abs that
are the focus of the experimental approach.
总结
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)
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Arthur M Mercurio其他文献
Arthur M Mercurio的其他文献
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{{ truncateString('Arthur M Mercurio', 18)}}的其他基金
Integrin Regulation of Non-apoptotic Death in Breast Cancer
整合素对乳腺癌非凋亡死亡的调节
- 批准号:
10196990 - 财政年份:2018
- 资助金额:
$ 38.32万 - 项目类别:
Integrin Regulation of Non-apoptotic Death in Breast Cancer
整合素对乳腺癌非凋亡死亡的调节
- 批准号:
10439666 - 财政年份:2018
- 资助金额:
$ 38.32万 - 项目类别:
Nanosensor-Based Phenotypic Screening for Precision Therapy of Cancer Stem Cells
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- 批准号:
9371612 - 财政年份:2017
- 资助金额:
$ 38.32万 - 项目类别:
Mechanisms of Carcinoma Differentiation and Invasion
癌分化和侵袭的机制
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8658042 - 财政年份:2012
- 资助金额:
$ 38.32万 - 项目类别:
Mechanisms of Carcinoma Differentiation and Invasion
癌分化和侵袭的机制
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8507623 - 财政年份:2012
- 资助金额:
$ 38.32万 - 项目类别:
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