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）：该临床前研究计划的总体目标是开发和评估新型多模式肿瘤治疗方案在转移性castatation castatration耐药性前列腺癌（MCRPC）模型中的总体生存方案的有效性。该研究计划具有四个特定的技术目标：»在CRPC的特征模型中用作单药治疗时，确定放射性标记177LU-BB2R拮抗剂的最大有效剂量（MED）和治疗效率。这将通过结合体内药代动力学分析并在CRPC的特征模型中进行177LU-BB2R拮抗剂的剂量试验来实现这一实现。将确定单个内部器官射击剂量测定估计值以及最低有效剂量（MED），其主要目标是确定最佳放射治疗剂量以治疗CRPC。评估多模式CRPC靶向放射疗法的体外 /体内协同作用以及在CRPC细胞系中结合紫杉烷化疗（Docetaxel vs.Cabazitaxel）的效率。这将使用体外细胞的活力和clogenicssess来评估药物组合的细胞毒性和协同作用（Docetaxel/177lu-BB2R拮抗剂与Cabazitaxel/177LU-BB2R拮抗剂）以评估CRPC细胞对治疗的影响。将使用CRPC的CRPC的侧面，胫骨和转移性异种移植模型来评估177LU-BB2R靶向放射疗法的体内协同作用和效率，并结合紫杉烷化疗（Docetaxel vs.Cabazitaxel）评估肿瘤反应（软组织和骨转移酶），并确定了crpc的转移性异常的特性，并确定了肿瘤的特性。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状态的有效生物标志物的实用性。评估多模式CRPC靶向放射疗法的体外 /体内协同作用以及新型酪氨酸激酶抑制剂治疗（Cabozantinib）的效率。该特定目标将与涉及紫杉烷的研究相似，目的是通过MET受体抑制来控制CRPC，以使用独特的放射敏化特性。拟议的研究将涉及使用侧面，胫骨和转移性CRPC异种模型的体内药代动力学分析和组合临床前治疗评估的结合结合体内药代动力学分析和组合临床前治疗评估。 »进行FDA IND促进研究，该研究将允许向177LU-BB2R拮抗剂的FDA提交物理赞助的IND。该目标将在整个资金期间进行，并将包括获得商业准备的CGMP产品，确定内部器官辐射剂量学，毒理学评估，制定和完善标准操作程序，以常规的临床临床准备177LU-BB2R拮抗剂的常规临床准备，并以17777 luuuuuuuuuuuuuuuuuuuuuuuuuuue the the Enders temerty productiations forment offorment offorment offorment offorment offorment offorment offorment offers。