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

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，主要包括姑息治疗。 我们建议开发具有显著延长药剂在前列腺癌组织中的停留时间的能力的放射性肽。预期前列腺癌停留时间的增加将显著增强放射治疗剂的有效性、安全性和临床转化潜力。目的：对于许多癌症受体靶向药物，在肿瘤部位缺乏停留时间是其临床转化的主要障碍。对于辐射应用，短停留时间 限制了肿瘤可达到的辐射剂量，从而限制了治疗益处。肿瘤缺氧是血管组织不良导致氧气输送至肿瘤部分受损的结果。在临床上，前列腺癌已被证明是最缺氧的癌症研究。该提案的目的是开发BB 2 r靶向药物，其利用低氧选择性捕获剂并利用前列腺癌的低氧性质来增加药物在肿瘤中的停留时间。我们期望，并已证明，缺氧选择性捕获剂（例如，2-硝基咪唑）引入BB 2 r靶向剂设计中将显著增加诊断和/或放射治疗剂在前列腺癌中的保留。如果成功的话，我们设想低氧选择性捕获剂的掺入将广泛适用于各种受体亲合剂，并导致提高各种癌症诊断和治疗平台的临床转化的功效、安全性和潜力。具体目标：（1）合成、表征和体外评估177 Lu-BB 2 r靶向的类似物，其具有低氧选择性捕获剂，（2）生物分布，缺氧增强的177 Lu-BB 2 r靶向类似物的体内组织学和分子成像研究和（3）缺氧增强的177 Lu-和90 Y-BB 2 r-的治疗评价前列腺癌异种移植和基因工程小鼠模型中的靶向类似物研究设计：本提案的第一个目的是合成、表征和评价缺氧增强的177 Lu-BB 2 r靶向剂的体外性质。体外评价将包括低氧和常氧条件下试剂的竞争性受体结合、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进行缺氧增强的177 Lu-BB 2 r靶向剂的初始体内评价。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。对于被认为是治疗的强候选物的低氧增强的BB 2 r靶向剂，这些剂将在PC-3-（HRE-Luc）和患者来源的异种移植模型以及前列腺癌的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价177 Lu和90 Y-BB 2 r靶向药物与多西他赛（一种常见的化疗药物和已知的前列腺癌治疗放射增敏剂）的联合治疗。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。.

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. .