Novel Therapeutic Approaches for Aggressive Prostate Cancer

侵袭性前列腺癌的新治疗方法

• 批准号: 10734381
• 负责人: Arthur M Mercurio
• 金额: $ 38.32万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10734381
• 关键词: Address; Adenocarcinoma; Aggressive behavior; Binding; Cells; Chemoresistance; Clinic; Clinical Trials; Coupled; Data; Goals; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune response; Immunocompetent; Immunosuppression; Invaded; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; NPR2 gene; Neoplasm Metastasis; Neuroendocrine Prostate Cancer; Neuroendocrine Therapy; Neuropilin-2; Outcome; Phenotype; Predisposition; Property; Reporting; Resistance; Role; Signal Transduction; Therapeutic; Toxic effect; Tumor Burden; Tumor Immunity; Tumor Promotion; Up-Regulation; Vascular Endothelial Growth Factors; Work; advanced prostate cancer; autocrine; cell killing; checkpoint inhibition; chemotherapy; effective therapy; exosome; humanized antibody; improved; inhibitor; manufacture; mortality; neoplastic cell; nonhuman primate; novel; novel therapeutic intervention; pressure; programmed cell death ligand 1; programmed cell death protein 1; prostate cancer model; receptor; response; stem cells; stemness; therapeutic target; translational potential; treatment strategy; tumor; tumor progression

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.

概括 该建议的目的是制定一种新型的治疗策略来治疗神经内分泌 前列腺癌（NEPC）有可能转化为诊所。 NEPC是一种激进的形式 前列腺癌与快速进展，抗药性和非常差的结果有关。 目前，没有有效治疗NEPC的疗法。这项修订的提案重点是假设 该程序性细胞死亡1配体（PD-L1）在干性和转移倾向中具有因果作用 与NEPC相关。尽管PD-L1以其在免疫抑制中的作用而闻名，但其肿瘤细胞 独立于免疫抑制的内在功能也会导致癌症进展。 具体而言，PD-L1已与肿瘤干，侵袭和转移有关，并且有 尽管有因果关系尚未是 证明。可以利用PD-L1的新功能来改善NEPC的治疗 令人信服的证据表明，VEGF/NRP2信号传导在前列腺癌中维持PD-L1的表达。 抑制VEGF/NRP2可降低干细胞特性，并促进更分化的表型 容易受到化学疗法的影响，并且该机制可能涉及降低PD-L1表达。另外， 可以使用人源化的mAb抑制VEGF与NRP2的结合。此mAb不会引起毒性 小鼠和非人类灵长类动物，正在用于临床试验中。值得注意的是，这种单元ab会减少 NEPC模型中PD-L1的表达显着。这些观察结果共同制定了一个中央 假设：PD-L1通过维持干性和促进转移（细胞）在NEPC中具有因果作用 自主PD-L1功能）和通过促进免疫细胞逃避（非细胞自主PD-L1功能）。 PD-L1的两个关键功能都可以通过将VEGF与NRP2结合的治疗靶向来阻止 与NEPC相关的发病率和死亡率。第一个具体目的将调查治疗策略 用于抑制PD-L1的肿瘤细胞固有功能，以减轻NEPC中的干和转移 阻止VEGF与NRP2的结合。第二个目标将调查针对PD-的治疗策略 NEPC中PD-L1的1依赖性和PD-1独立函数，通过阻止VEGF与NPR2的结合 使用免疫胜任模型。本提案中产生的数据有可能提供足够的 证明使用NRP2抑制剂的临床试验的证据，尤其是功能阻断ABS 是实验方法的重点。