Molecular Imaging Reagents for Prostate Cancer Theranostics

研发总结1 前列腺癌是美国男性癌症死亡的第二大原因。 死于前列腺癌的男性继续死于转移性阉割抵抗疾病。有一个迫切的需求 目的：寻找治疗转移性前列腺癌的有效方法。我们在BTRC的tr&d1的目的是成功地开发 原型机治疗分子成像平台寻求新的途径：(I)检测和靶向 粘着斑激酶(FAK)允许细胞迁移的机械转导途径(目标1a和b)，(Ii) 检测和消除激活的癌症相关成纤维细胞(CAF)在 前列腺癌前转移细胞外基质(ECM)的形成(AIM 2)，以及(Iii)形成前列腺特异性 抗原(PSMA)靶向纳米颗粒(NPs)携带siRNA下调程序性死亡配体1(PD-1) L1)与前药酶一起，利用免疫系统的激活，与局部细胞一起 杀伤，局部晚期和转移性前列腺癌(目标3)。光学和PET成像记者将整合 进入平台，实现体内纳米粒子的时空可视化，用于精准医学。PSMA， 一种在抗去势的PCa表面大量表达的II型整合膜蛋白， 晚期和转移性疾病，提供独特的优势，提供PSMA特异性NPs的有效 局部晚期或转移性前列腺癌的控制和治疗。这些研究将导致加速 FAK PET成像探针的研制将对近期临床翻译产生直接影响 正在进行的FAK抑制剂治疗试验的患者选择。癌细胞的机械运动是一种 侵袭和转移的先决条件。使用PSMA实现特定于PCA的FAK下调的NPS- 特定的递送将提供癌症特异性的细胞迁移下调，这是转移的关键步骤 卡斯卡德。同样，通过成像检测肿瘤中的CAF将比活组织检查提供明显的优势 在评估CAF数作为攻击性标志的标本中。用光疗消除CAF可能 提供减少或消除前列腺癌转移的策略。纳米粒子在提高免疫治疗中的研究进展 在PCA中通过语音学及其翻译将代表着该领域的重大进步，因为PCA已经 传统上对免疫疗法的反应不好。Tr&d1也将作为临床前验证核心 这将通过与CPS和其他研发部门的密切互动，开发和传播新的分子 将在全球范围内推进癌症精准医学的成像治疗药物。

SUMMARY for TR&D 1 Prostate cancer (PCa) is the second leading cause of death from cancer in men in the U.S. The vast majority of men dying of PCa continue to succumb to metastatic castration-resistant disease. There is a compelling need to find effective treatments for metastatic PCa. Our purpose in TR&D1 of the BTRC is to successfully develop prototype theranostic molecular imaging platforms to pursue novel avenues of (i) detecting and targeting the focal adhesion kinase (FAK) mechanotransduction pathway that allow cells to migrate (Aims 1a and b), (ii) detecting and eliminating activated cancer associated fibroblasts (CAFs) that play an important role in the formation of a prometastatic extracellular matrix (ECM) in PCa (Aim 2), and (iii) developing prostate specific antigen (PSMA)-targeted nanoparticles (NPs) to deliver siRNA to downregulate programmed death ligand 1 (PD- L1) together with a prodrug enzyme, to exploit the activation of the immune system, together with localized cell killing, in locally advanced and metastatic PCa (Aim 3). Optical and PET imaging reporters will be integrated into the platforms to achieve spatial and temporal visualization of the NPs in vivo for precision medicine. PSMA, a type II integral membrane protein that is abundantly expressed on the surface of PCa in castration-resistant, advanced and metastatic disease, provides a unique advantage to deliver PSMA-specific NPs for effective control and treatment of locally advanced or metastatic PCa. These studies will result in the accelerated development of FAK PET imaging probes with near term clinical translation that will have a direct impact on the selection of patients for ongoing FAK inhibitor treatment trials. Mechanical movement of cancer cells is a prerequisite for invasion and metastasis. NPs that achieve PCa-specific downregulation of FAK using PSMA- specific delivery will provide cancer-specific downregulation of cell migration, a key step in the metastatic cascade. Similarly, detection of CAFs in tumors with imaging will provide a distinct advantage over biopsy specimens in evaluating CAF numbers as a marker of aggressiveness. CAF elimination with phototherapy may provide a strategy to reduce or eliminate PCa metastasis. The development of NPs to improve immunotherapy in PCa through theranostics and their translation will represent a significant advance in this field since PCa has traditionally not responded well to immunotherapy. TR&D1 will also serve as the Pre-Clinical Validation Core that will, through close interactions with the CPs and other TR&Ds, develop and disseminate novel molecular imaging theranostic agents that will advance precision medicine of cancer worldwide.