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 ?-particle emitter 177Lu that are in multi-center clinical trials. In Europe, there have been preliminary trials using the ?-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 ?-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 ?-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 ?-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.

Public Health Relevance

Existing molecular radiotherapeutics for managing prostate cancer can become ineffective due to resistance mechanisms on the one hand, but if less susceptible to resistance, can be effective yet highly toxic on the other. We have chosen to leverage many years of experience in designing imaging and therapeutic agents targeting the prostate-specific membrane antigen (PSMA) to develop an agent radiolabeled with 211At, an alpha-particle emitter, which may have a higher therapeutic index than existing PSMA-targeted beta-particle (177Lu) and alpha- particle (225Ac) emitting agents. The goal of this project is to perform a low dose human imaging study using the 211At-labeled lead agent for human dosimetry to define a starting dose ultimately for a phase I clinical trial in patients with metastatic castration-resistant prostate cancer (mCRPC).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA184228-06
Application #
9886363
Study Section
Imaging Probes and Contrast Agents Study Section (IPCA)
Program Officer
Capala, Jacek
Project Start
2014-05-01
Project End
2024-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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