Molecular and Clinical Correlates with Prostate-Specific Membrane Antigen (PSMA)-Targeted Radionuclide Therapy
Abstract
Radiation is a cornerstone in the treatment of patients with prostate cancer (PC), including the bone-targeting radioactive drug, radium-223 (Xofigo®). Although radium-223 improves both the quality and duration of the lives of men, the radioactive particle only gets near PC in bone and skips tumors outside of bone. On the other hand, targeted radionuclide therapy (TRT) attaches a radioactive isotope to an antibody or small molecule that binds only to a specific cancer-related molecule on a tumor cell (a “lock and key” scenario, where the antibody or small molecule resembles the key that will only recognize a very specific lock in the cancer cell). As it turns out, nearly all PC tumors have a specific “lock,” called prostate-specific membrane antigen (PSMA), that is absent in most other places in the body. This means a PSMA-targeted antibody drug can get to and deliver drug to PC cells anywhere in the body, including the bone, largely bypassing normal organs. We have completed a series of studies utilizing PSMA TRT called 177Lu-J591, which includes a radioactive particle attached to a PSMA-seeking antibody. We are now further optimizing PSMA-TRT with additional novel clinical trials. In addition to treatment for patients, PSMA agents can also be used for more accurate imaging of cancer. Standard scans cannot always distinguish cancer from benign areas. PSMA imaging can also show changes in response to help more accurately guide therapy. As stated above, we can also exploit the tumor-exclusive nature of PSMA to deliver therapy preferentially to PC tumors. Therefore, PSMA-TRT has become one of the “hottest” areas in clinical therapeutics for men with advanced PC, in part evidenced by the recent inclusion of “Imaging and TRT” as a Prostate Cancer Research Program (PCRP) Focus Area. This represents not only a more targeted (or tumor-specific) drug, but also a biomarker that can be followed in patients non-invasively (with imaging scans). It makes sense that delivering potent radiation doses to nearly all tumors via PSMA should result in excellent responses and outcomes; the fact is that some do exceptionally well, but not all respond. We have a dataset from men treated with PSMA-TRT since 2003 with long-term follow-up; most have available tumor and blood specimens. We are also collecting specimens in our current PSMA-TRT optimization studies, with all data contributing to a “common data element” database that is extremely useful for analysis. We will look at clinical characteristics that associate with response (or lack thereof) and outcomes on PSMA-TRT, including sites of cancer spread, PSA level, Gleason score, blood test parameters, etc. Using samples, we will look at the DNA and RNA building blocks of prostate tumors to identify genes and other molecular biomarkers that are associated with response (or lack thereof) to PSMA-TRT. We have developed a prostate cancer specific assay to look at tumor DNA in blood (circulating tumor DNA or ctDNA) and will analyze ctDNA before and after PSMA-TRT to identify dynamic characteristics associated with clinical benefit using this “liquid biopsy” platform. Some patients do exceptionally well following PSMA-TRT, and studies have shown that radiation may lead to an immune response. We believe that some patients will generate a significant immune response following PSMA-TRT. We also predict that an immune response from PSMA-TRT will associate with exceptional outcomes. We will use stored and new blood samples to compare pre- and post-treatment immune response. One of the most well-described markers of “immunogenic cell death” is utilized in tissue, but it is often difficult to obtain routine biopsies in men with advanced PC before and after treatment. We have developed a way to assess this marker (called calreticulin) in circulating tumor cells (CTCs) obtained via a blood sample before and after PSMA-TRT. Not only might this approach identify those that generate a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810527
Entities
People
- Scott T Tagawa
Organizations
- United States Army
- Weill Cornell Medicine