Targeted Radiotherapy/Chemotherapy Treatment of Prostate Cancer

前列腺癌的靶向放化疗

• 批准号: 8539129
• 负责人: TIMOTHY J. HOFFMAN
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539129
• 关键词: Beta Particle; Biological Assay; Biological Markers; Bombesin Receptor; Cell Survival; Cells; Cessation of life; Cities; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Contracts; Coupling; Cyclic GMP; Data; Deposition; Developed Countries; Development; Disease; Disseminated Malignant Neoplasm; Dose; Drug Combinations; Drug Kinetics; Effectiveness; Endotoxins; Evaluation; Funding; Goals; Human; In Vitro; Individual; Iowa; Laboratories; Malignant neoplasm of prostate; Maximum Tolerated Dose; Mediating; Metastatic Neoplasm to the Bone; Methods; Modeling; Organ; PC3 cell line; Patients; Peptides; Performance; Phase; Physicians; Pilot Projects; Positron-Emission Tomography; Preparation; Principal Investigator; Procedures; Property; Quality Control; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radioisotopes; Radiolabeled; Radiometry; Radiopharmaceuticals; Receptor Inhibition; Recommendation; Research; Rodent; Running; Schedule; Sterility; Targeted Radiotherapy; Taxane Compound; Therapeutic; Time; Toxic effect; Toxicology; Treatment Efficacy; Treatment Protocols; Tyrosine Kinase Inhibitor; Universities; Veterans; Vial device; Xenograft Model; Xenograft procedure; base; cancer diagnosis; castration resistant prostate cancer; chemotherapy; cytotoxicity; docetaxel; dosimetry; improved; in vivo; internal radiation; male; meetings; men; molecular imaging; neoplastic cell; novel; pre-clinical; pre-clinical research; programs; prostate cancer cell; public health relevance; radiochemical; radiotracer; receptor; research study; response; small molecule; soft tissue; synergism; taxane; tumor; tumor growth

DESCRIPTION (provided by applicant): The overall goal of this preclinical research program is to develop and evaluate the efficacy of a novel multi-modal tumor treatment regimen on overall survival in models of metastatic castration resistant prostate cancer (mCRPC). The research program has four specific technical objectives: ¿ Determine the maximum effective dose (MED) and therapeutic efficacy of radiolabeled 177Lu-BB2r antagonists when used as single agent therapy in xenograft models of CRPC. This will be accomplished by performing a combination of in vitro cell viability and clonogenic assays combined with in vivo pharmacokinetic analysis and escalating dose trials of a 177Lu-BB2r antagonist in xenograft models of CRPC. Individual internal organ radiation dosimetry estimates will be determined as well as a minimum effective dose (MED) with the primary goal of determining an optimum radiotherapeutic dose for treatment of CRPC. ¿ Evaluate in vitro / in vivo synergism and efficacy of multi-modal CRPC targeted radiotherapy combined with taxane chemotherapy (Docetaxel vs. Cabazitaxel) in CRPC cell lines. This will be accomplished using in vitro cell viability and clonogenic assays to assess cytotoxicity and synergism of the drug combinations (Docetaxel/177Lu-BB2r antagonist vs. Cabazitaxel/177Lu-BB2r antagonist) to evaluate CRPC cell responsiveness to treatment. In vivo synergism and efficacy of 177Lu-BB2r targeted radiotherapy combined with taxane chemotherapy (Docetaxel vs. Cabazitaxel) will be assessed using flank, tibial, and metastatic xenograft models of CRPC to evaluate tumor response (soft tissue and bone metastases) and identify which radiotherapy/taxane combination has superior tumor control properties. We will also concurrently evaluate the utility of using molecular imaging of BB2r expression as an effective biomarker of disease presence and tumor status. ¿ Evaluate the in vitro /in vivo synergism and efficacy of multi-modal CRPC targeted radiotherapy combined with novel tyrosine kinase inhibitor therapy (Cabozantinib). This specific objective will be carried out similarly to the studes involving taxanes with the goal of utilizing the unique radiosensitizing properties as a result of MET receptor inhibition to control CRPC. The proposed studies will involve a combination of in vitro cell viability and clonogenic assays combined with in vivo pharmacokinetic analysis and combination preclinical therapeutic assessment utilizing flank, tibial, and metastatic CRPC xenograft models. ¿ Perform FDA IND enabling studies that will permit submission of a physician sponsored IND to the FDA of a 177Lu-BB2r antagonist. This objective will be carried out over the course of the funding period and will include obtaining commercially prepared cGMP product, determining internal organ radiation dosimetry, toxicology evaluation, development and refinement of a standard operating procedure for the routine clinical preparation of 177Lu-BB2r antagonist, and performance of required preparative product runs to demonstrate that the 177Lu-BB2r antagonist meets end product specifications for human use.

描述（由申请人提供）： 该临床前研究项目的总体目标是开发和评价一种新型多模式肿瘤治疗方案对转移性去势抵抗性前列腺癌（mCRPC）模型总生存期的疗效。该研究计划有四个具体的技术目标：确定放射性标记的177 Lu-BB 2 r拮抗剂在CRPC异种移植模型中用作单药治疗时的最大有效剂量（MED）和治疗功效。这将通过在CRPC异种移植模型中进行体外细胞活力和克隆形成测定与体内药代动力学分析和177 Lu-BB 2 r拮抗剂的递增剂量试验的组合来实现。将确定个体内部器官辐射剂量测定估计值以及最小有效剂量（MED），主要目标是确定治疗CRPC的最佳辐射剂量。 评价CRPC细胞系中多模式CRPC靶向放疗联合紫杉烷化疗（多西他赛vs卡巴他赛）的体外/体内协同作用和疗效。这将使用体外细胞活力和克隆形成测定来完成，以评估药物组合（多西他赛/177 Lu-BB 2 r拮抗剂对比卡巴他赛/177 Lu-BB 2 r拮抗剂）的细胞毒性和协同作用，从而评估CRPC细胞对治疗的响应性。将使用CRPC的侧腹、胫骨和转移性异种移植模型评估177 Lu-BB 2 r靶向放疗与紫杉烷化疗组合（多西他赛vs卡巴他赛）的体内协同作用和功效，以评估肿瘤反应（软组织和骨转移）并鉴定哪种放疗/紫杉烷组合具有上级肿瘤控制特性。我们还将同时评估使用BB 2 r表达的分子成像作为疾病存在和肿瘤状态的有效生物标志物的效用。 评估多模式CRPC靶向放疗联合新型酪氨酸激酶抑制剂治疗（卡博替尼）的体外/体内协同作用和疗效。这一特定目标将与涉及紫杉烷类的研究类似地进行，目的是利用MET受体抑制导致的独特放射增敏特性来控制CRPC。拟定的研究将涉及体外细胞活力和克隆形成试验与体内药代动力学分析的组合，以及利用侧腹、胫骨和转移性CRPC异种移植模型进行的临床前治疗评估。 进行FDA IND使能研究，允许向FDA提交医生申办的177 Lu-BB 2 r拮抗剂IND。这一目标将在资助期内实现，包括获得商业制备的cGMP产品，确定内部器官辐射剂量学，毒理学评价，开发和完善177 Lu-BB 2 r拮抗剂常规临床制备的标准操作规程，和所需制备产品运行的性能，以证明177 Lu-BB 2 r拮抗剂符合人用最终产品规格。