Novel Therapeutic Approaches for Aggressive Prostate Cancer

侵袭性前列腺癌的新治疗方法

基本信息

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.
概括 该提案的目标是开发一种新的治疗策略来治疗神经内分泌疾病 前列腺癌(NEPC)有可能转化为临床。 NEPC 是一种积极的形式 前列腺癌与快速进展、治疗耐药和预后极差有关。 目前,尚无治疗 NEPC 的有效疗法。这个修订后的提案侧重于假设 程序性细胞死亡 1 配体 (PD-L1) 在干性和转移倾向中具有因果作用 与 NEPC 相关。尽管 PD-L1 因其在免疫抑制中的作用而闻名,但它的肿瘤细胞 独立于免疫抑制的内在功能也可能导致癌症进展。 具体而言,PD-L1 与肿瘤干性、侵袭和转移有关,并且有 间接证据表明它有助于 NEPC 中的这些功能,尽管因果作用尚未确定 证明了。 PD-L1的这一新功能可用于改善基于NEPC的治疗 令人信服的证据表明 VEGF/NRP2 信号传导维持前列腺癌中 PD-L1 的表达。 抑制 VEGF/NRP2 会降低干细胞特性并促进更加分化的表型 对化疗敏感,其机制可能与降低 PD-L1 表达有关。另外,一个 人源化 mAb 可抑制 VEGF 与 NRP2 的结合。该 mAb 不会引起毒性 小鼠和非人类灵长类动物,正在生产用于临床试验。值得注意的是,这种单克隆抗体会减少 PD-L1在NEPC模型中显着表达。这些观察共同形成了一个中心 假设:PD-L1 通过维持干性和促进转移而在 NEPC 中发挥因果作用(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 的这两个关键功能可以通过 VEGF 与 NRP2 结合的治疗靶向来阻断,从而改善 与 NEPC 相关的发病率和死亡率。第一个具体目标将研究治疗策略 用于抑制肿瘤细胞 PD-L1 的内在功能,以减轻 NEPC 的干细胞性和转移,涉及 阻断 VEGF 与 NRP2 的结合。第二个目标是研究针对 PD-的治疗策略 通过阻断 VEGF 与 NPR2 的结合,NEPC 中 PD-L1 的 1 依赖性和 PD-1 独立功能 使用免疫能力模型。本提案中生成的数据有可能提供足够的信息 证据证明启动使用 NRP2 抑制剂的临床试验是合理的,特别是功能阻断抗体 是实验方法的重点。

项目成果

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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
基于纳米传感器的表型筛选用于癌症干细胞的精准治疗
  • 批准号:
    9371612
  • 财政年份:
    2017
  • 资助金额:
    $ 38.32万
  • 项目类别:
Integrin splicing and cancer stem cell fate
整合素剪接和癌症干细胞命运
  • 批准号:
    9055381
  • 财政年份:
    2015
  • 资助金额:
    $ 38.32万
  • 项目类别:
VEGF Signaling in Mammary Tumorigenesis
乳腺肿瘤发生中的 VEGF 信号转导
  • 批准号:
    8406744
  • 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
  • 批准号:
    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
  • 批准号:
    8507623
  • 财政年份:
    2012
  • 资助金额:
    $ 38.32万
  • 项目类别:
VEGF Signaling in Mammary Tumorigenesis
乳腺肿瘤发生中的 VEGF 信号转导
  • 批准号:
    8507653
  • 财政年份:
    2012
  • 资助金额:
    $ 38.32万
  • 项目类别:
VEGF signaling in Mammary Tumorigenesis
乳腺肿瘤发生中的 VEGF 信号传导
  • 批准号:
    10152521
  • 财政年份:
    2012
  • 资助金额:
    $ 38.32万
  • 项目类别:
VEGF signaling in Mammary Tumorigenesis
乳腺肿瘤发生中的 VEGF 信号传导
  • 批准号:
    9922868
  • 财政年份:
    2012
  • 资助金额:
    $ 38.32万
  • 项目类别:

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Control mechanisms of lung adenocarcinoma by SGLT2 inhibitors for treating diabetes mellitus.
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