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Pb-212 Peptide Receptor Targeted Prostate Cancer Therapy

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
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-12 至 2023-08-31

项目摘要

项目成果

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中文摘要
翻译
这个临床前研究项目的总体目标是开发和评估靶向α的疗效
英文摘要
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.
期刊论文(4)
专著(0)
科研奖励(0)
会议论文
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
影响因子: --
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
影响因子: --
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
ShEEP Request for VA BIC MRI Cryoprobe
BLR&D Research Career Scientist Award Application
BLR&D Research Career Scientist Award Application
BLR&D Research Career Scientist Award Application
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