Novel Antivascular Therapy for Aggressive Metastatic Renal Cell Carcinoma: A Radiotheranostic Approach
Abstract
Kidney cancer, particularly the clear cell renal cell carcinoma (ccRCC) subtype, is reliant on a robust blood supply. The prevention or destruction of new blood vessel formation within these tumors has demonstrated an ability to treat them effectively. However, like other cancers, ccRCC can develop resistance to existing agents. Although immunotherapy has also been effective at treating ccRCC, such treatment is often at the expense of significant side-effects, and only a minority of patients have long-term response. For these reasons, we need new and better therapies for ccRCC. Prostate-specific membrane antigen (PSMA) is a protein found on the surfaces of the cells that make up the blood vessels in ccRCC tumors. Recently, we and others have demonstrated that we can use PSMA-based imaging of patients to visualize metastatic ccRCC, suggesting that PSMA could be a target for a new type of therapy. A recent report on a large cohort of patient specimens demonstrated that PSMA expression in ccRCC indicates a bad prognosis, further highlighting the potential role of PSMA as a target for therapy. PSMA-targeted molecules that release a type of high-energy radiation known as alpha particles could be used for radiotherapy when bound to the blood vessels in the ccRCC tumors. In our proposal, we will work to develop a PSMA-targeted alpha-particle agent for radiotherapy. The radiation associated with alpha particles is highly lethal to nearby cells but also does not travel very far, thus making our proposed approach ideal for killing blood vessel cells of metastatic ccRCC while sparing normal cells from side-effects. We believe that PSMA-targeted alpha-radiotherapy compound will accumulate in tumor and rapidly clear from the rest of the body and will have high treatment efficacy. The companion PSMA imaging test will allow us to non-invasively select patients that are most likely to benefit from alpha-radiotherapy. Features of the proposal include: (1) The unique structural features of our agents and their application to treat ccRCC is innovative. (2) Given that PSMA expression is mainly on the blood vessels and not on the tumor cells themselves, we will develop experiments to evaluate surgical RCC specimens for PSMA expression patterns. (3) Our lead therapeutic agent has been selected from extensive pre-existing data from our group and is currently being evaluated in multiple institutions in patients with prostate cancer (NCT03490838). (4) Our first alpha-radiotherapy compound of this class has been evaluated in a year-long preclinical acute and chronic toxicity study in mice to determine the maximum safe dose. All proposed alpha therapy in animal models will be investigated at = 50% of the maximum safe dose to ensure a clinically safe and effective dose for immediate clinical translation of the agent after the completion of the project. (4) In the clinical trial follow-on to this project, we will be able to use PSMA-based imaging to select those patients who are most likely to respond to PSMA-targeted alpha-radiotherapy, allowing us to maximize benefit while avoiding needless side-effects in those patients who would not benefit from the therapy. The short-term impact of the project is the development and validation of new PSMA-targeted alpha-radiotherapy for ccRCC in preclinical models, e.g., mice. The fact that a number of drugs targeting blood vessels have shown clinical efficacy for this disease gives great hope that PSMA-based alpha-radiotherapy can further improve clinical outcomes, specifically for patients with metastatic disease from this aggressive type of cancer. Because of how such targeted radiotherapy directly damages the DNA, this treatment will be less susceptible than currently available therapeutic agents to evasion by tumor resistance. As long as the radiation gets to the target cells, they can do nothing to escape it. The targeted manner in which the therapy is delivered will reduce poten
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110921
Entities
People
- Steven P Rowe
Organizations
- Johns Hopkins University
- United States Army