Novel Therapeutic Approaches for Aggressive Prostate Cancer

总结 该提案的目标是开发一种新的治疗策略，用于治疗神经内分泌 前列腺癌（NEPC），有可能转化为临床。NEPC是一种侵略性的 前列腺癌与快速进展、对治疗的抵抗和非常差的结果相关。 目前，没有有效的治疗NEPC的疗法。这一修订后的提案侧重于假设 程序性细胞死亡1配体（PD-L1）在干细胞和转移倾向中具有因果作用， 与NEPC有关。尽管PD-L1最为人所知的是其在免疫抑制中的作用，但其肿瘤细胞 不依赖于免疫抑制的内在功能也可促进癌症进展。 具体而言，PD-L1与肿瘤的干性、侵袭和转移有关， 间接证据表明，它有助于NEPC中的这些功能，尽管因果关系尚未确定。 演示。PD-L1的这种新功能可用于改善NEPC的治疗， 令人信服的证据表明，VEGF/NRP 2信号转导维持前列腺癌中PD-L1的表达。 抑制VEGF/NRP 2降低了干细胞的特性，并促进了更分化的表型， 易受化疗影响，其机制可能涉及减少PD-L1表达。此外， 可获得抑制VEGF与NRP 2结合的人源化mAb。该mAb不会引起毒性， 小鼠和非人灵长类动物，并正在制造用于临床试验。值得注意的是，这种mAb减少 PD-L1在NEPC模型中的表达显著增加。总之，这些观察形成了一个中心的 假设：PD-L1通过维持干细胞和促进转移（细胞 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的两种关键功能都可以通过治疗性靶向VEGF与NRP 2的结合来阻断，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一种治疗策略 用于抑制肿瘤细胞PD-L1的内在功能，以减轻NEPC的干性和转移， 阻断VEGF与NRP 2的结合。第二个目标是研究针对PD的治疗策略， 1-通过阻断VEGF与NPR 2的结合，在NEPC中发挥PD-L1的依赖性和PD-1非依赖性功能 使用免疫模型。本提案中生成的数据有可能提供足够的 有证据证明使用NRP 2抑制剂，特别是功能阻断Ab， 是实验方法的重点。

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.