权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Small Molecule PSMA-Targeted Alpha Therapy

小分子 PSMA 靶向阿尔法疗法

基本信息

批准号：
10411890
负责人：
MARTIN G POMPER
金额：
$ 36.22万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411890
关键词：
Ablation Alpha Particle Emitter Alpha Particles Antigen Targeting Beta Particle Biodistribution Biological Blood Bone Diseases Catabolism Characteristics Chemistry Clinical Trials Cohort Studies Data Discipline of Nuclear Medicine Disease Dose Drug Kinetics Europe Evaluation FOLH1 gene Frequencies Gallium Goals Human Image Immunohistochemistry Knowledge Label Lacrimal gland structure Lead Linear Energy Transfer Lutetium Malignant Neoplasms Malignant neoplasm of prostate Mediating Metabolism Metastatic Neoplasm to the Bone Molecular Multi-Institutional Clinical Trial Mus Patients Pharmaceutical Chemistry Phase Phase I Clinical Trials Positioning Attribute Positron-Emission Tomography Procedures Prostate Quality of life Radiation therapy Radioactivity Radiochemistry Radiolabeled Radiometry Radionuclide therapy Recommendation Regimen Resistance Salivary Glands Specimen Structure Survival Rate Testing Therapeutic Clinical Trial Therapeutic Index Therapeutic Studies Tissues Toxic effect Urine Work Xenograft procedure adduct analog base castration resistant prostate cancer cell killing clinical investigation design dosimetry experience human imaging human subject imaging agent imaging study in vivo lipophilicity meetings men molecular imaging neoplastic cell programs radiotracer resistance mechanism response small molecule targeted agent targeted treatment treatment effect tumor

项目摘要

Project Summary Despite the expanding array of new targeted agents to treat castration-resistant prostate cancer (CRPC), the disease remains incurable with nearly half of men with this form of PC developing bone metastases at two years. Metastatic bone disease carries a one-year survival rate of ~40%. Targeting the prostate-specific membrane antigen (PSMA) with small molecules for imaging and radionuclide therapy (RT) of prostate and other cancers has revitalized the field of nuclear medicine. Novartis has recently acquired [177Lu]R2, developed by us, and [177Lu]PSMA-617, two PSMA-targeted RT labeled with the β-particle emitter 177Lu that are in multi-center clinical trials. In Europe, there have been preliminary trials using the α-particle emitting agent [225Ac]PSMA-617 that have shown substantial treatment effects, even in patients that became resistant to the corresponding 177Lu- labeled compound. However, these encouraging responses to targeted α-particle RT (TAT) often came at the expense of immediate ablation of the salivary and lacrimal glands, with long-term toxicities unknown. Accordingly, despite widespread efforts, translational RT for PC is at a crucial stage, having yet to identify an agent that provides durable responses without compromising quality of life. The approach that we shall take in this competing renewal is to extend our basic work focusing on 211At, which emits a single α-particle per decay, to a low-dose, pharmacokinetic clinical trial. We hypothesize that 211At will provide an intermediate between the minimally toxic, but less effective 177Lu and the more powerful but potentially damaging 225Ac, which emits a total of four α-particles per decay that are difficult to control in vivo and promote the aforementioned toxicity. Our goal is to have an agent with an optimal therapeutic index by combining the high linear energy transfer (LET) tumor cell kill of 211At with greater control of toxicity through molecular design for salutary pharmacokinetics and dosing strategies. Preliminary in vivo data with our lead 211At-labeled compound, [211At]VK-02-90-Lu, indicates much lower off-target toxicity than for a related 225Ac-labeled adduct, confirmed by immunohistochemistry, with similar survival characteristics. The current program is intended to provide the experimental rationale and data for an IND-enabling therapeutic study.

项目总结