Targeted Radiotherapy/Chemotherapy Treatment of Prostate Cancer

前列腺癌的靶向放化疗

基本信息

批准号：
8669719
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
项目类别：
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/8669719
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

项目摘要

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估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）模型总体生存的疗效。该研究项目有四个具体的技术目标：确定放射性标记的 177Lu-BB2r 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) 和治疗效果这将通过体外细胞活力和克隆形成测定与体内药代动力学相结合来实现。将确定 CRPC 异种移植模型中 177Lu-BB2r 拮抗剂的分析和剂量递增试验，以及确定最低有效剂量。 (MED) 的主要目标是确定治疗 CRPC 的最佳放射治疗剂量。评估多模式 CRPC 靶向放疗联合紫杉烷化疗（多西紫杉醇与卡巴他赛）在 CRPC 细胞系中的体外/体内协同作用和疗效。这将通过体外细胞活力和克隆形成分析来评估细胞毒性和协同作用。药物组合（多西他赛/177Lu-BB2r 拮抗剂与卡巴他赛/177Lu-BB2r 拮抗剂）评估 CRPC 细胞对将使用 CRPC 的侧腹、胫骨和转移性异种移植模型来评估 177Lu-BB2r 靶向放疗联合紫杉烷化疗（多西紫杉醇与卡巴他赛）的体内协同作用和疗效，以评估肿瘤反应（软组织和骨转移）并识别。我们还将同时评估使用 BB2r 表达的分子成像作为疾病存在和肿瘤的有效生物标志物的效用。地位。评估多模式 CRPC 靶向放疗与新型酪氨酸激酶抑制剂疗法（卡博替尼）相结合的体外/体内协同作用和疗效。这一具体目标将与涉及紫杉烷类的研究类似，旨在利用独特的放射增敏特性。作为通过抑制 MET 受体来控制 CRPC 的结果，拟议的研究将结合体外细胞活力和克隆形成测定，以及体内药代动力学分析和临床前联合治疗。利用侧翼、胫骨和转移性 CRPC 异种移植模型进行评估。进行 FDA IND 授权研究，允许向 FDA 提交医生赞助的 177Lu-BB2r 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、确定内脏器官辐射。 177Lu-BB2r 拮抗剂常规临床制备的剂量测定、毒理学评估、标准操作程序的开发和完善，以及所需制备产品运行的性能，以证明177Lu-BB2r 拮抗剂符合人类使用的最终产品规格。