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

描述(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。 我们建议开发能够显著延长该制剂在前列腺癌组织中的停留时间的放射治疗多肽。前列腺癌滞留时间的增加有望大大提高放射治疗剂的有效性、安全性和临床转译的潜力。目的：对于许多受体靶向的抗癌药物来说，缺乏在肿瘤部位的停留时间是其临床转译的主要障碍。在放射治疗应用方面，较短的停留时间 限制肿瘤可达到的放射治疗剂量，从而限制治疗效益。肿瘤缺氧是血管组织不良导致部分肿瘤的氧气输送受损的结果。在临床上，前列腺癌已被证明是所研究的最低氧的癌症之一。这项建议的目的是开发BB2r靶向药物，利用低氧选择性捕捉剂，并利用前列腺癌的低氧特性来增加药物在肿瘤中的停留时间。我们预计，并已经证明，将低氧选择性捕捉剂(例如，2-硝基咪唑)纳入BB2r靶向药物设计将显著增加前列腺癌诊断和/或放射治疗药物的保留。如果成功，我们预计低氧选择性捕捉剂的整合将广泛适用于各种受体亲和剂，并导致各种癌症诊断和治疗平台的有效性、安全性和临床转译潜力的提高。具体目标：(1)合成、表征和体外评价含有低氧选择性捕捉剂的177Lu-BB2r靶向类似物；(2)低氧增强型177Lu-BB2r靶向类似物在体内的生物分布、组织学和分子成像研究；(3)低氧增强型177Lu-BB2r和90Y-BB2r靶向类似物在异种移植和基因工程小鼠前列腺癌模型中的疗效评价研究设计：本建议的第一个目的是合成、表征和评价低氧增强型177Lu-BB2r靶向制剂的体外性质。体外评估将包括药物在低氧和常氧条件下的竞争性受体结合、内化、外排和代谢鉴定。根据足够的体外结果，低氧增强的177Lu-BB2r靶向药物将在PC-3-(HRE-Luc)异种移植小鼠模型中进行初步的体内评估。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药物的缺氧增强型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对177Lu-和90Y-BB2r靶向药物与多西紫杉醇的联合评估，多西紫杉醇是前列腺癌治疗中一种常见的化疗和放射增敏剂。作为治疗研究的一部分，将确定最大耐受量，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. .