GRPR/PSMA Targeting Agents for Prostate Cancer Diagnosis

用于前列腺癌诊断的 GRPR/PSMA 靶向药物

• 批准号: 9229985
• 负责人: Charles J Smith
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229985
• 关键词: Adverse effects; Advocate; American; American Cancer Society; Antibodies; Antigen Targeting; Benign Prostatic Hypertrophy; Binding; Biological; Biological Markers; Bioprobe; Biopsy; Blood; Bombesin Receptor; Cancer Etiology; Caring; Cells; Cessation of life; Chemicals; Chronic; Clinic; Clinical; Clinical Trials; Compassion; Detection; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Discipline of Nuclear Medicine; Disease; Dose; Drug Kinetics; Early Diagnosis; Ensure; Evaluation; FOLH1 gene; Family; Fostering; Genomics; Goals; Health; Human; Image; In Vitro; Investigation; Knowledge; Life; Ligands; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Metabolic; Metastatic Prostate Cancer; Methods; Mission; Modeling; Molecular Models; Molecular Target; Mus; Nature; Needle biopsy procedure; Neoplasm Metastasis; Non-Invasive Cancer Detection; Operative Surgical Procedures; Pain; Palliative Care; Patients; Peptides; Pharmacology; Primary Neoplasm; Prostate-Specific Antigen; Prostatic Neoplasms; Publishing; Radiation; Radioisotopes; Radiolabeled; Reference Values; Refractory; Research; Serum; Services; Staging; Surface; System; Time; Toxic effect; Translations; Ultrasonography; United States; United States Department of Veterans Affairs; Veterans; X-Ray Computed Tomography; acute toxicity; anatomic imaging; androgen deprivation therapy; base; cancer biomarkers; cancer cell; cancer diagnosis; clinical Diagnosis; cost; design; differential expression; digital; disability; education research; imaging potential; improved; in vivo; innovation; male; men; molecular imaging; molecular modeling; mortality; mouse model; novel; novel diagnostics; outcome forecast; peptide hormone; precision medicine; prevent; prostate cancer cell; radioligand; receptor; rectal; single photon emission computed tomography; small molecule; success; targeted agent; targeted biomarker; tumor; unnecessary treatment

According to the American Cancer Society, prostate cancer will account for an estimated 180,890 new cases and 26,120 deaths in 2016, continuing to be the most commonly diagnosed cancer and second-leading cause of cancer death in men in the United States. This research application provides rationale toward the design and development of new diagnostic agents based upon two well-validated biomarkers for early and late-stage detection of prostate cancer and is central to the research mission of the United States Department of Veterans' Affairs of seeking fundamental knowledge to enhance health, lengthen life, and reduce illness and disability of American veterans. The primary objective of this research application is to develop a metabolically stable, bivalent (dual receptor targeting), gastrin releasing peptide receptor/prostate-specific membrane antigen (GRPR/PSMA) targeting radioligand for Single Photon Emission Computed Tomography (SPECT) imaging of GRPR- and PSMA- positive prostate tumors. The GRPR and PSMA are well-validated prostate cancer biomarkers that are expressed in very high numbers on the surfaces of most prostate cancers. Because prostate cancer cells seem to differentially express specific receptors depending upon factors that may include chronicity and metastatic nature, it logically follows that a compound capable of targeting more than one biomarker would have the potential of binding to both early and chronic/metastatic stages of prostate cancer, enabling a more prompt and accurate diagnostic profile for both stages of disease. This application contains four discrete and well-delineated specific objectives: 1. Synthesis, purification, and characterization of new bivalent GRPR/PSMA-targeting radioligands. 2. To validate the cell targeting capacity of the GRPR/PSMA-targeting probes in vitro in GRPR/PSMA- expressing cells. 3. To evaluate the pharmacokinetics, pharmacology, stability, and SPECT imaging potential of the targeting probes in GRPR/PSMA-expressing prostate tumors in mice. 4. Quantitative pharmacokinetic tumor modeling and single dose acute toxicity study of the most viable molecular imaging candidate.

据美国癌​​症协会估计，前列腺癌将导致 180,890 例新病例 2016 年有 26,120 人死亡，仍然是最常见的癌症和第二大原因 美国男性癌症死亡人数。这项研究应用为设计提供了理论依据 基于两种经过充分验证的早期和晚期生物标志物开发新的诊断剂 前列腺癌的检测，是美国卫生部研究任务的核心 退伍军人事务部致力于寻求基础知识，以增强健康、延长寿命、减少疾病和 美国退伍军人的残疾。 本研究应用的主要目标是开发一种代谢稳定的二价（双受体） 靶向）、胃泌素释放肽受体/前列腺特异性膜抗原（GRPR/PSMA）靶向 用于 GRPR- 和 PSMA- 的单光子发射计算机断层扫描 (SPECT) 成像的放射性配体 前列腺肿瘤呈阳性。 GRPR 和 PSMA 是经过充分验证的前列腺癌生物标志物 在大多数前列腺癌的表面上以非常高的数量表达。因为前列腺癌细胞 似乎根据可能包括慢性和 转移性质，从逻辑上讲，能够靶向多个生物标志物的化合物将 有可能与前列腺癌的早期和慢性/转移阶段结合，从而使更多 对疾病的两个阶段进行及时、准确的诊断。 该应用程序包含四个离散且明确的具体目标： 1. 新型二价 GRPR/PSMA 靶向放射性配体的合成、纯化和表征。 2. 体外验证 GRPR/PSMA 靶向探针的细胞靶向能力 表达细胞。 3. 评估靶向药物的药代动力学、药理学、稳定性和 SPECT 成像潜力 小鼠体内表达 GRPR/PSMA 的前列腺肿瘤的探针。 4. 最可行的定量药代动力学肿瘤模型和单剂量急性毒性研究 分子成像候选人。