Molecular Imaging Reagents for Prostate Cancer Theranostics

用于前列腺癌治疗诊断的分子成像试剂

• 批准号: 10226208
• 负责人: Zaver M. Bhujwalla
• 金额: $ 23.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226208
• 关键词: Antibodies; Antigen Targeting; Autoimmunity; Biological Sciences; Biopsy Specimen; CTLA4 gene; Cancer Detection; Cancer Etiology; Castration; Cause of Death; Cells; Cessation of life; Clinical; Collagen; Collagen Fiber; Complex; Cytosine deaminase; Desmoplastic; Development; Diagnosis; Disease; Disease Resistance; Down-Regulation; Enzymes; Esters; Extracellular Matrix; FOLH1 gene; Fiber; Fibroblasts; Flucytosine; Fluorouracil; Focal Adhesion Kinase 1; Focal Adhesions; Funding Mechanisms; Future; Goals; Image; Immune response; Immune system; Immunosuppression; Immunotherapy; Infection; Integral Membrane Protein; Integrins; Interferons; Invaded; Label; Malignant Neoplasms; Malignant neoplasm of prostate; Mechanics; Metastatic Prostate Cancer; Metastatic to; Molecular; Molecular Target; Monoclonal Antibodies; Movement; Neoplasm Metastasis; Optical reporter; Optics; Pathway interactions; Patient Selection; Patients; Phenotype; Phototherapy; Play; Positron-Emission Tomography; Prodrugs; Prostate-Specific Antigen; Reagent; Recurrence; Reporter; Resistance; Resources; Role; Signaling Protein; Site; Small Interfering RNA; Source; Stromal Cells; Surface of the Prostate; T-Lymphocyte; Tissues; Translations; Validation; Visualization; antibody conjugate; base; cancer cell; cancer imaging; cancer therapy; cell killing; cell motility; checkpoint inhibition; clinical translation; clinically translatable; effective therapy; extracellular; frontier; imaging agent; imaging modality; imaging platform; imaging probe; immune activation; immune checkpoint; improved; in vivo; kinase inhibitor; mechanotransduction; men; molecular imaging; mortality; nanoparticle; nanoparticle delivery; novel; overexpression; pre-clinical; precision medicine; precision oncology; programmed cell death ligand 1; programmed cell death protein 1; prostate cancer metastasis; prostate cancer progression; prototype; response; success; theranostics; treatment trial; tumor; tumor microenvironment; tumor progression

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.

TR&D 1摘要 前列腺癌（PCa）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去势抵抗性疾病。现在迫切需要 寻找转移性前列腺癌的有效治疗方法我们在BTRC的TR&D1中的目的是成功开发 原型治疗诊断分子成像平台，以寻求新的途径，（i）检测和靶向 允许细胞迁移的粘着斑激酶（FAK）机械转导途径（目的1a和B），（ii） 检测和消除活化的癌症相关成纤维细胞（CAF），其在癌症的发生中起重要作用。 在PCa中形成促转移性细胞外基质（ECM）（目的2），和（iii）发展前列腺特异性 抗原（PSMA）靶向纳米颗粒（NP）递送siRNA以下调程序性死亡配体1（PD-L1）。 L1）与前药酶一起，以利用免疫系统的激活，与局部细胞一起， 杀死，在局部晚期和转移性PCa（目的3）。将集成光学和PET成像报告器 到平台中，以实现精确医学的体内NP的空间和时间可视化。PSMA， 一种II型整合膜蛋白，其在去势抗性中的PCa表面上大量表达， 晚期和转移性疾病，提供了递送PSMA特异性NP的独特优势，用于有效治疗 控制和治疗局部晚期或转移性PCa。这些研究将加速 开发FAK PET成像探头，并进行短期临床转化，这将对 选择患者进行FAK抑制剂治疗试验。癌细胞的机械运动是一种 是侵袭和转移的先决条件。使用PSMA实现FAK的PCA特异性下调的NP- 特异性递送将提供细胞迁移的癌症特异性下调，细胞迁移是转移性肿瘤发生的关键步骤。 级联。同样，通过成像检测肿瘤中的CAF将提供优于活检的明显优势 标本在评估CAF数字作为侵略性的标志。光疗消除CAF可能 提供减少或消除PCa转移的策略。开发NP以改善免疫治疗 在PCa中通过治疗诊断学及其翻译将代表该领域的重大进展，因为PCa 传统上对免疫疗法反应不佳。TR&D1也将作为临床前验证核心 这将通过与CP和其他TR& D的密切互动，开发和传播新的分子 成像治疗诊断剂，将推动全球癌症的精确医学。