Enhancement of BB2r-Targeted Radiotherapy for Prostate Cancer Utilizing Hypoxia-S

利用 Hypoxia-S 增强 BB2r 靶向放射治疗前列腺癌

• 批准号: 8697922
• 负责人: Jered C Garrison
• 金额: $ 31.23万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697922
• 关键词: 90Y; Affinity; Autoradiography; Binding; Biodistribution; Blood Vessels; Bombesin; Cancer Patient; Chemotherapy-Oncologic Procedure; Clinical; Diagnostic; Dose; Drug Design; Drug Targeting; Effectiveness; Evaluation; Genetically Engineered Mouse; Goals; Histology; Histopathology; Human; Hypoxia; ICAM1 gene; Imaging Techniques; In Vitro; Investigation; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Maximum Tolerated Dose; Metabolism; Metastatic Prostate Cancer; Molecular Weight; Mus; Nature; Oxygen; Palliative Care; Patients; Peptides; Pharmaceutical Preparations; Population; Property; Prostate; Prostatic Neoplasms; Radiation therapy; Radiation-Sensitizing Agents; Radionuclide Imaging; Research Design; Roentgen Rays; Safety; Site; Targeted Radiotherapy; Technology; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Translations; X-Ray Computed Tomography; Xenograft Model; Xenograft procedure; advanced disease; analog; azomycin; base; cancer cell; cancer therapy; clinical care; design; docetaxel; in vivo; molecular imaging; mouse model; peptide hormone; prostate cancer model; public health relevance; receptor; receptor binding; residence; single photon emission computed tomography; small molecule; therapeutic evaluation; tumor

DESCRIPTION (provided by applicant): Currently, therapeutic treatment options for metastatic prostate cancer patients are exceedingly limited and consist largely of palliative care. We propose to develop radiotherapeutic peptides that have the capability of dramatically extending the residence time of the agent in prostate cancer tissue. This increase in prostate cancer residence time would be expected to substantially enhance the effectiveness, safety and potential for clinical translation of the radiotherapeutic agent. Objective: For many receptor-targeted agents for cancer, the lack of residence time at the tumor site is a major impediment to their clinical translation. With respect to radiotherapeutic applications, the short residence time limits the achievable radiotherapeutic dose for the tumor thus limiting the therapeutic benefit. Tumor hypoxia is the result of poor vascular organization leading to the impaired delivery of oxygen to portions of the tumor. Clinically, prostate cancer has been shown to be among the most hypoxic of cancers investigated. The objective of this proposal is to develop BB2r-targeted agents that utilize hypoxia-selective trapping agents and exploit the hypoxic nature of prostate cancer to increase the residence time of the agent in the tumor. We expect, and have demonstrated, that the incorporation of hypoxia-selective trapping agents (e.g., 2-nitroimidazoles) into the BB2r-targeted agent design will substantially increase the retention of diagnostic and/or radiotherapeutic agents in prostate cancer. If successful, we envision that incorporation of hypoxia- selective trapping agents would be widely applicable for a variety of receptor-avid agents and lead to an increase to the efficacy, safety and potential for clinical translation of a wide variety of diagnostic and therapeutic platforms for cancer. Specific Aims: (1) Synthesize, Characterize and Evaluate in vitro 177Lu-BB2r-Targeted Analogs Incorporating Hypoxia-Selective Trapping Agents, (2) Biodistribution, Histological and Molecular Imaging Studies of Hypoxia Enhanced 177Lu-BB2r-targeted Analogs in vivo and (3) Therapeutic Evaluation of Hypoxia Enhanced 177Lu- and 90Y-BB2r-targeted Analogs in Xenograft and Genetically Engineered Mouse Models of Prostate Cancer Study Design: The first aim of this proposal is to synthesize, characterize and evaluate the in vitro properties of hypoxia-enhanced 177Lu-BB2r-targeted agents. In vitro evaluation will include competitive receptor binding, internalization, efflux and metabolism identification of the agents under both hypoxic and normoxic conditions. Upon adequate in vitro results, the initial in vivo evaluation of the hypoxia-enhanced 177Lu-BB2r-targeted agents will be carried out in a PC-3-(HRE-Luc) xenograft mouse model. These in vivo investigations will include biodistribution, human dose estimates, histopathology and molecular imaging studies. For hypoxia- enhanced BB2r-targeted agents that are deemed to be strong candidates for therapy, these agents will undergo therapeutic investigation in PC-3-(HRE-Luc) and patient-derived xenograft models as well as genetically-engineered mouse models of prostate cancer. These therapy studies will include evaluation of 177Lu- and 90Y-BB2r targeted agents in combination with docetaxel, a common chemotherapeutic and known radiosensitizer in prostate cancer treatment. As part of the therapy studies, maximum tolerated doses will be determined and toxicities will be assessed by histopathological analysis. .

描述（由申请人提供）：目前，转移性前列腺癌患者的治疗选择非常有限，并且主要包括姑息治疗。 我们建议开发能够显着延长药剂在前列腺癌组织中的停留时间的放射治疗肽。前列腺癌停留时间的增加预计将大大提高放射治疗剂的有效性、安全性和临床转化潜力。目的：对于许多受体靶向癌症药物来说，在肿瘤部位缺乏停留时间是其临床转化的主要障碍。对于放射治疗应用，停留时间短 限制了肿瘤可达到的放射治疗剂量，从而限制了治疗效果。肿瘤缺氧是血管组织不良导致向肿瘤部分输送氧气受损的结果。临床上，前列腺癌已被证明是所研究的缺氧程度最高的癌症之一。该提案的目的是开发 BB2r 靶向药物，利用缺氧选择性捕获剂并利用前列腺癌的缺氧性质来增加药物在肿瘤中的停留时间。我们预计并已经证明，将缺氧选择性捕获剂（例如 2-硝基咪唑）纳入 BB2r 靶向剂设计将大大增加诊断和/或放射治疗剂在前列腺癌中的保留。如果成功，我们预计缺氧选择性捕获剂的掺入将广泛适用于各种受体亲和剂，并提高各种癌症诊断和治疗平台的功效、安全性和临床转化潜力。具体目标：(1) 体外合成、表征和评估结合缺氧选择性捕获剂的 177Lu-BB2r 靶向类似物，(2) 体内缺氧增强型 177Lu-BB2r 靶向类似物的生物分布、组织学和分子成像研究，以及 (3) 缺氧增强型 177Lu- 和 177Lu-BB2r 靶向类似物的治疗评估 前列腺癌异种移植和基因工程小鼠模型中的 90Y-BB2r 靶向类似物研究设计：本提案的第一个目的是合成、表征和评估缺氧增强的 177Lu-BB2r 靶向药物的体外特性。体外评估将包括在低氧和常氧条件下药物的竞争性受体结合、内化、外排和代谢鉴定。在获得足够的体外结果后，将在 PC-3-(HRE-Luc) 异种移植小鼠模型中对缺氧增强的 177Lu-BB2r 靶向药物进行初步体内评估。这些体内研究将包括生物分布、人体剂量估计、组织病理学和分子成像研究。对于被认为是强有力的治疗候选者的缺氧增强 BB2r 靶向药物，这些药物将在 PC-3-(HRE-Luc) 和患者来源的异种移植模型以及前列腺癌基因工程小鼠模型中进行治疗研究。这些治疗研究将包括评估 177Lu- 和 90Y-BB2r 靶向药物与多西紫杉醇（一种前列腺癌治疗中常见的化疗药物和已知的放射增敏剂）的组合。作为治疗研究的一部分，将确定最大耐受剂量并通过组织病理学分析评估毒性。 。