PSMA’s enzymatic activity as new target for Prostate Cancer diagnosis and therapy

总结。问题：激素疗法仍然是前列腺癌(PC)的标准治疗方法。而当 大多数患者最初对治疗有反应，最终会进展为致命的抗去势PC(CRPC) 在6至12个月内。在进展过程中，正常的雄激素来源被 即使在没有激素的情况下，也会引发PC的生长，这使得现阶段的治疗非常困难。建议 解决方案：我们将利用一种新发现的前列腺特异性膜抗原(PSMA)的生物学功能 为PC开发一种全新的个性化治疗策略，与现有的显著不同 治疗。PSMA的高水平在最具侵袭性的PC中可见，是病情进展的预测指标。 然而，PSMA的生物学作用仍不清楚。我们的建议是基于我们最近的范式转变 发现PSMA提供一种迄今未知的致癌信号功能，其中它的酶活性 触发错综复杂的细胞内信号转导系统，通过激活 PI3K/AKT/mTORC-1以及mTORC-2信号转导通路。用图形绘制了PSMA的接口 主要的生物信号在PC中级联，我们在这里提供了一种新的疗法来扰乱这些主要的信号 小路。重要的是，抑制PSMA对小鼠的存活有好处。我们同时开发了一个同伴 一种廉价、简便的体外生物发光法诊断和监测前列腺癌的成像方法 现成的样品。在本实验中，谷氨酸荧光素(GluLuc)被PSMA特异性地切割以释放 利用台式检测系统检测尿液/前列腺液中的荧光素酶。我们有 已经在小鼠和患者身上评估了这种检测方法，并表明它优于PSA的黄金标准 级别。在这里，Aim 1将专注于我们的配套成像分析。我们将测量PSMA释放的荧光素 表达的前列腺液尿(EPS/U)或尿液，并将生物发光信号与局部和 转移性肿瘤的负担和生长。Aim 2将探索抑制PSMA作为PC的单一疗法或 与雄激素抑制相结合。由于抑制PSMA活性将导致荧光素的释放减少， 我们将把信号的减少与肿瘤的反应联系起来。我们将重新调整PSMA抑制剂的用途， 因中枢神经系统渗透率低而被放弃的已证实的中枢神经系统疾病的安全性。在目标3中，我们将探索 If PSMA抑制可用于CRPC的治疗和预防转移形成。我们还将测试它是否 可以延缓去势抵抗的发生。与目标2一样，我们将使用台式化验监测治疗情况。肿瘤 我们的工作意义重大，因为它描绘了一条全新的道路 根据PSMA的特定生物学功能进行PC治疗。PSMA的潜在生物学基础是高度 创新，因为尽管它具有重大的生物学后果，但从未被探索过。此外，我们 还展示了一种创新、便捷且廉价的体外台式方法来诊断、监控PC和 监测疗法。最终，这将使所有的PC患者受益，特别是那些CRPC患者。

SUMMARY. The problem: Hormone therapy remains the standard treatment for prostate cancer (PC). While most patients initially respond to therapy, they will ultimately progress to lethal castration-resistant PC (CRPC) within 6 to 12 months. During progression, canonical sources of androgens are replaced with mechanisms that trigger PC growth, even in the absence of hormones, making therapy at this stage very difficult. Proposed solution: We will utilize a newly discovered biological function of prostate-specific membrane antigen (PSMA) to develop an entirely new personalized therapeutic strategy for PC that is significantly different from existing therapies. High levels of PSMA are seen in most aggressive forms of PC and are a predictor for progression. However, the biological role of PSMA remains unknown. Our proposal is based on our recent paradigm-shifting discovery that PSMA provides a so far unknown oncogenic signaling function, where its enzymatic activity triggers an intricate intracellular signaling repertoire, promoting cancer growth through activation of the Pi3K/AKT/mTORC-1 as well as the mTORC-2 signaling cascades. Having charted the interface of PSMA with the main biological signaling cascades in PC, we provide here a novel therapy that disrupts these major signaling pathways. Importantly, inhibition of PSMA led to a survival benefit in mice. We developed in parallel a companion imaging assay to diagnose and monitor PC with a cheap and facile ex vivo bioluminescence-based assay from readily available samples. In this assay glutamated luciferein (GluLuc) is cleaved specifically by PSMA to release luciferin that can be detected by luciferase in urine/prostatic secretions with a bench top assay system. We have already evaluated this assay in mice and patients and have shown that it is superior to the gold standard of PSA levels. Here, Aim 1 will focus on our companion imaging assay. We will measure luciferin released by PSMA in expressed prostatic secretions urine (EPS/U) or urine and correlate the bioluminescence signal with local and metastatic tumor burden and growth. Aim 2 will explore inhibition of PSMA as therapy for PC as monotherapy or in combination with androgen inhibition. Since inhibition of PSMA activity will lead to reduced release of luciferin, we will correlate the reduction of signal with the tumor response. We will repurpose PSMA inhibitors, with a proven safety profile for CNS disease that were abandoned due to low CNS penetration. In Aim 3, we will explore if PSMA inhibition can be used as therapy of CRPC and to prevent metastasis formation. We will also test if it can delay onset of castration resistance. As in Aim 2, we will monitor therapy with the benchtop assay. Tumor growth will be interrogated with MR and PET imaging Our work is significant, as it charts an entirely new path for PC therapy based on the specific biological function of PSMA. The underlying biology of PSMA is highly innovative, as it has never been explored in spite of its significant biological consequences. Furthermore, we also demonstrate an innovative, facile, and inexpensive ex vivo benchtop approach to diagnose, monitor PC and monitor therapy. Ultimately, this will benefit all patients with PC, particularly those with CRPC.