Targeted Radiotherapy/Chemotherapy Treatment of Prostate Cancer

描述(由申请人提供)： 这项临床前研究计划的总体目标是开发和评估一种新的多模式肿瘤治疗方案对转移性去势耐受前列腺癌(MCRPC)模型的总生存率的疗效。该研究计划有四个具体的技术目标：确定放射性标记的177Lu-BB2r拮抗剂在CRPC异种移植模型中作为单药治疗时的最大有效剂量(MED)和治疗效果。这将通过在CRPC异种移植模型中进行体外细胞活性和克隆形成试验、体内药代动力学分析和177Lu-BB2r拮抗剂的递增剂量试验相结合的方式来实现。将确定个人内脏辐射剂量估算以及最小有效剂量(MED)，主要目标是确定治疗CRPC的最佳放射治疗剂量。[目的]评价多模式CRPC靶向放疗联合紫杉烷化疗(多西紫杉醇与卡巴紫杉醇)在体外和体内对CRPC细胞株的协同作用和疗效。这将通过体外细胞存活率和克隆形成试验来评估药物组合(多西紫杉醇/177Lu-BB2r拮抗剂与Cabazitaxel/177Lu-BB2r拮抗剂)的细胞毒性和协同作用，以评估CRPC细胞对治疗的反应性。将使用CRPC的侧翼、胫骨和转移性异种移植模型来评估177Lu-BB2r靶向放射治疗与紫杉烷化疗(多西紫杉醇vs Cabazitaxel)的体内协同作用和疗效，以评估肿瘤反应(软组织和骨转移)，并确定哪种放射治疗/紫杉烷组合具有更好的肿瘤控制特性。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记物的实用性。[目的]评价多模式CRPC靶向放疗联合新型酪氨酸激酶抑制剂(Cabozantinib)治疗的体内外协同作用和疗效。这一特定的目标将类似于涉及紫杉烷的研究，目的是利用由于MET受体抑制而产生的独特的放射增敏特性来控制CRPC。建议的研究将结合体外细胞存活率和克隆形成试验，结合体内药代动力学分析，以及利用侧翼、胫骨和转移性CRPC异种移植模型进行联合临床前治疗评估。？执行FDA IND启用研究，该研究将允许医生赞助的IND向FDA提交177Lu-BB2r拮抗剂。这一目标将在整个资助期内进行，将包括获得商业化制备的cGMP产品、测定内脏辐射剂量、毒理学评估、制定和完善177Lu-BB2r拮抗剂常规临床制剂的标准操作程序，以及所需制备产品的运行情况，以证明177Lu-BB2r拮抗剂符合人类使用的最终产品规格。

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.