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

基本信息

批准号：
8845527
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
项目类别：
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/8845527
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 Health 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 Radiopharmaceuticals 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 receptor receptor binding residence single photon emission computed tomography small molecule therapeutic evaluation tumor

项目摘要

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方法受到极大限制，主要由姑息治疗组成。我们建议开发放射治疗肽，这些肽具有显着延长前列腺癌组织中剂的停留时间的能力。预计前列腺癌停留时间的这种增加将大大提高放射治疗剂的临床翻译的有效性，安全性和潜力。目的：对于许多针对癌症的受体靶向药物，肿瘤部位缺乏停留时间是其临床翻译的主要障碍。关于放射治疗应用，停留时间很短限制了可实现的放射治疗剂量的肿瘤，从而限制了治疗益处。肿瘤缺氧是血管组织不良的结果，导致氧气流向部分肿瘤的递送受损。在临床上，前列腺癌已被证明是研究中最低氧的癌症之一。该提案的目的是开发利用缺氧选择性诱捕剂并利用前列腺癌的缺氧性质以增加肿瘤中药剂的停留时间的靶向BB2R靶向药物。我们期望并已经证明，将缺氧选择性捕获剂（例如2-硝基咪唑）掺入BB2R靶向的剂设计将大大增加诊断和/或放射性疗法剂在前列腺癌中的保留。如果成功的话，我们会设想掺入缺氧 - 选择性诱捕剂将广泛适用于各种避免受体的药物，并提高了癌症多种诊断和治疗平台的临床翻译功效，安全性和潜力。具体目的：（1）合成，表征和评估体外177LU-BB2R靶向的类似物，结合了缺氧选择性捕获剂，（2）生物分布，低氧的生物分布，组织学和分子成像研究增强了177LU-BB2R靶向的177LU-BB2R靶向类似物（3），并具有177次触发性和（3）的（3）对3）的影响。异种移植物和前列腺癌研究设计的基因设计的小鼠模型中的90Y-BB2R类似物设计：该建议的第一个目的是综合，表征和评估低氧增强的177LU-BB2R靶向剂的体外特性。体外评估将包括竞争受体结合，内在化，外排和代谢在低氧和常氧条件下的鉴定。根据足够的体外结果，将在PC-3-（HRE-LUC）异种移植小鼠模型中对低氧增强177LU-BB2R靶向药物进行初始体内评估。这些体内研究将包括生物分布，人剂量估计，组织病理学和分子成像研究。对于被认为是强大治疗的BB2R靶向药物，这些药物将在PC-3-（HRE-LUC）和患者衍生的异种移植模型以及前列腺癌的遗传引擎化小鼠模型中接受治疗研究。这些疗法研究将包括评估177LU-和90Y-BB2R靶向剂以及多西他赛（Docetaxel），这是前列腺癌治疗中常见的化学治疗和已知放射敏剂。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。。