Pb-212 Peptide Receptor Targeted Prostate Cancer Therapy

Pb-212 肽受体靶向前列腺癌治疗

• 批准号: 10247544
• 负责人: TIMOTHY J. HOFFMAN
• 金额: $ 35.03万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-12 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247544
• 关键词: 90Y; Androgen Receptor; Androgens; Animal Model; Apoptosis; Bombesin Receptor; Cell Cycle Proteins; Cell Line; Cell model; Cell-Mediated Cytolysis; Cessation of life; Chemoresistance; Clinical; Clinical Trials; Complex; Contracts; Cyclic GMP; DNA Repair; Data; Dependence; Development; Disease; Dose; Drug Kinetics; Endotoxins; Evaluation; Funding; Goals; Growth; Human; In Vitro; Individual; Investigation; Isotopes; Lead; Malignant neoplasm of prostate; Maximum Tolerated Dose; Measures; Methods; Neoplasm Metastasis; Organ; PC3 cell line; Patients; Peptide Receptor; Peptides; Performance; Pharmacotherapy; Phase 0/1 Clinical Trial; Physicians; Positron-Emission Tomography; Preparation; Procedures; Production; Progressive Disease; Prostate Cancer therapy; Prostatic Neoplasms; Quality Control; RNA Splicing; Radiation therapy; Radio; Radiochemistry; Radioisotopes; Radiolabeled; Radiometry; Radionuclide Generators; Radiopharmaceuticals; Radium-224; Recommendation; Research; Resistance; Running; Series; Sterility; Technology; Tissues; Toxicology; Treatment Efficacy; United States; VCaP; Validation; Variant; Vial device; Xenograft Model; abiraterone; base; cancer diagnosis; cytotoxicity; docetaxel; efficacy evaluation; imaging biomarker; in vivo; male; meetings; men; novel; pre-clinical; pre-clinical research; programs; protein expression; radiochemical; receptor; response; scale up; systemic toxicity; targeted treatment; therapeutic biomarker; treatment response; tumor

The overall goal of this preclinical research program is to develop and evaluate the efficacy of targeted alpha therapy (TAT) using an alpha emitting radiolabeled peptide antagonist which targets the bombesin receptor (BB2r) expressed in human prostate cancer. The research program has four specific technical objectives:  Synthesis & Validation of 212Pb-RM2: The goals of this objective are to establish and optimize methods for synthesizing 212Pb-RM2 in high yield and purity starting with 212Pb obtained from commercially available 224Ra/212Pb radionuclide generators. Utilizing automated radiochemistry technology, routine SOP’s will be developed for the efficient production of clinical grade 212Pb-RM2. This will also entail developing procedures for assessing the quality control to assure that the final product meets FDA requirements for pH, sterility, and bacterial endotoxins.  Evaluate Efficacy of 212Pb-RM2 In Vitro: The utility of 212Pb-RM2 will be assessed across a panel of human PC cell lines representing the spectrum of androgen dependence/independence as well as a panel of chemotherapy resistant cell lines that are resistant to docetaxel, enzalutamide, and abiraterone. Several chemotherapy resistant cell lines will be created during the course of this study. The effects of TAT on each cell line will be evaluated by assessing cytotoxicity, clonogenicity, DNA damage & repair, apoptosis, cell cycle, and protein expression of the targeted receptor, (BB2r), the androgen receptor (AR), and the most prevalent androgen receptor splice variant in PC,(ARV7).  Evaluate Efficacy of 212Pb-RM2 In Vivo: Initially, the in vivo stability of 212Pb-RM2 will be assessed followed by determination of individual organ, tissue, and tumor radiation dosimetry based on 212Pb-RM2 pharmacokinetic data obtained using prostate cancer xenograft models. The maximum tolerated dose (MTD) of 212Pb-RM2 will be determined prior to performance of therapeutic efficacy evaluation. Employing a series of CRPC xenograft models (flank, tibial, and systemic), the efficacy of 212Pb-RM2 in controlling and reducing focal and systemic PC growth will be evaluated. Concurrent PET imaging using 68Ga-RM2 will be performed to assess BB2r expression concurrent with BB2r targeted treatment to validate the imaging biomarker as an accurate measure of treatment efficacy.  Perform FDA IND Enabling Studies: Data from these studies will be used to prepare a physician sponsored IND for submission to the FDA of the TAT agent, 212Pb-RM2. 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, obtaining commercial single species toxicology evaluation data, development and refinement of a standard operating procedure for the routine automated clinical preparation of 212Pb-RM2, and performance of required preparative product scale-up runs to demonstrate that 212Pb-RM2 can be prepared in quantities and purity necessary to meet expected clinical demands.

这项临床前研究计划的总体目标是开发和评估靶向α-羟色胺的疗效。 使用靶向蛙皮素受体的α发射放射性标记肽拮抗剂的TAT疗法 （BB 2 r）在人前列腺癌中表达。该研究计划有四个具体的技术目标： 212 Pb-RM 2的合成与验证：本目标的目标是建立和优化方法 用于以高产率和纯度合成212 Pb-RM 2，所述212 Pb-RM 2是从可商购获得的212 Pb开始的 224 Ra/212 Pb放射性核素发生器。利用自动化放射化学技术，将常规SOP 为临床级212 Pb-RM 2的高效生产而开发。这也将需要制定程序 用于评估质量控制，以确保最终产品符合FDA对pH值、无菌性和 细菌内毒素 体外评价212 Pb-RM 2的有效性：212 Pb-RM 2的效用将在一组受试者中进行评估。 代表雄激素依赖性/非依赖性谱的人PC细胞系以及一组 在一些实施方案中，本发明涉及对多西他赛、恩杂鲁胺和阿比特龙具有抗性的化疗抗性细胞系。几 在本研究过程中将产生化疗抗性细胞系。达特对每个细胞的影响 将通过评估细胞毒性、克隆形成、DNA损伤和修复、细胞凋亡、细胞周期和 靶向受体（BB 2 r）、雄激素受体（AR）和最普遍的 雄激素受体剪接变异体（ARV 7）。 评价212 Pb-RM 2的体内有效性：首先，将评估212 Pb-RM 2的体内稳定性 随后基于212 Pb-RM 2测定单个器官、组织和肿瘤的辐射剂量 使用前列腺癌异种移植模型获得的药代动力学数据。最大耐受剂量（MTD） 将在进行疗效评价前测定212 Pb-RM 2。采用一系列 CRPC异种移植模型（侧腹、胫骨和全身），212 Pb-RM 2在控制和减少局灶性 并评价全身PC生长。将使用68 Ga-RM 2进行同步PET成像，以评估 BB 2 r表达与BB 2 r靶向治疗同时进行，以验证成像生物标志物作为准确的 治疗效果的测量。 执行FDA IND使能研究：这些研究的数据将用于准备医生 申办的IND，用于向FDA提交达特制剂212 Pb-RM 2。这一目标将在 资助期的过程，包括获得商业化制备的cGMP产品， 内脏辐射剂量学，商业单种毒理学评价数据获取，发展 以及212 Pb-RM 2常规自动化临床制备的标准操作程序的改进， 以及所需制备产品放大运行的性能，以证明可以制备212 Pb-RM 2 其数量和纯度必须满足预期的临床需求。

项目成果

Evaluation of 72Se/72As generator and production of 72Se for supplying 72As as a potential PET imaging radionuclide.

评估 72Se/72As 发生器和生产 72Se，以提供 72As 作为潜在 PET 成像放射性核素。

• DOI: 10.1016/j.apradiso.2018.10.026
• 发表时间: 2019
• 期刊: Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine
• 作者: Feng,Yutian;Phipps,MichaelD;Phelps,TimE;Okoye,NkemakonamC;Baumeister,JakobE;Wycoff,DonaldE;Dorman,EricF;Wooten,ALake;Vlasenko,Vladislav;Berendzen,AshleyF;Wilbur,DScott;Hoffman,TimothyJ;Cutler,CathyS;Ketring,AlanR;Ju
• 通讯作者: Ju

A New, Second Generation Trithiol Bifunctional Chelate for 72,77As: Trithiol(b)-(Ser)2-RM2.

72,77As 的新型第二代三硫醇双功能螯合物：三硫醇(b)-(Ser)2-RM2。

• DOI: 10.1021/acs.bioconjchem.0c00658
• 发表时间: 2021
• 期刊: Bioconjugate chemistry
• 影响因子: 4.7
• 作者: NajafiKhosroshahi,Firouzeh;Feng,Yutian;Ma,Li;Manring,Simon;Rold,TammyL;Gallazzi,FabioA;Kelley,StevenP;Embree,MaryF;Hennkens,HeatherM;Hoffman,TimothyJ;Jurisson,SilviaS
• 通讯作者: Jurisson,SilviaS

Synthesis and preclinical evaluation of a novel fluorine-18 labeled small-molecule PET radiotracer for imaging of CXCR3 receptor in mouse models of atherosclerosis.

一种新型氟 18 标记小分子 PET 放射性示踪剂的合成和临床前评估，用于动脉粥样硬化小鼠模型中 CXCR3 受体的成像。

• DOI: 10.21203/rs.3.rs-2539952/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Alluri,SantoshR;Higashi,Yusuke;Berendzen,Ashley;Grisanti,LaurelA;Watkinson,LisaD;Singh,Kamlendra;Hoffman,TimothyJ;Carmack,Terry;Devanny,ElizabethA;Tanner,Miles;Kil,Kun-Eek
• 通讯作者: Kil,Kun-Eek