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.

摘要 这项提议的目标是开发一种治疗神经内分泌的新策略。 前列腺癌(NEPC)有可能转化为临床。NEPC是一种具有侵略性的形式 前列腺癌与进展快、治疗抵抗和预后非常差有关。 目前，还没有有效的治疗方法来治疗NEPC。这项修订后的提案侧重于假设 程序性细胞死亡1配体(PD-L1)在干细胞分化和转移倾向中起因果作用 与NEPC相关联。尽管PD-L1因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可能导致癌症的进展。 具体地说，PD-L1与肿瘤的干性、侵袭和转移有关，并且有 间接证据表明，它对NEPC的这些功能有贡献，尽管因果关系尚未确定 演示了。PD-L1的这一新功能可以被开发来改善NEPC的治疗 令人信服的证据表明，血管内皮生长因子/NRP2信号支持前列腺癌中PD-L1的表达。 抑制VEGF/NRP2会降低干细胞的特性，并促进更分化的表型，即 对化疗敏感，其机制可能涉及减少PD-L1的表达。此外，还有一个 人源化单抗可以抑制血管内皮生长因子与NRP2的结合。该单抗不会对小鼠产生毒性 老鼠和非人类灵长类动物，正在制造用于临床试验。值得注意的是，这种单抗会减弱 PD-L1在NEPC模型中的表达明显增强。总而言之，这些观察形成了一个中心 假设：PD-L1通过维持干性和促进转移(细胞)在NEPC中起因果作用 自主PD-L1功能)和促进免疫细胞逃避(非细胞自主PD-L1功能)。 PD-L1的这两个关键功能可以通过治疗靶向与NRP2结合来阻断，以改善 与NEPC相关的发病率和死亡率。第一个具体目标是研究治疗策略。 为了抑制肿瘤细胞PD-L1的内在功能以减轻NEPC的干性和转移，涉及 阻断血管内皮生长因子与NRP2的结合。第二个目标是研究针对帕金森病的治疗策略。 PD-L1通过阻断VEGF与NPR2的结合在NEPC中的1依赖和PD-1非依赖性功能 使用免疫能力模型。本提案中产生的数据有可能提供足够的 使用NRP2抑制剂，特别是功能阻断抗体启动临床试验的证据 是实验方法的重点。