There’s an exciting new development in treating metastatic prostate cancer (PCa) that no longer responds to hormone therapy. Such cancer is clinically called metastatic castration-resistant prostate cancer, or mCRPC. There is currently no cure when PCa reaches this stage, but new drugs and immunotherapies can prolong life.

Researchers are exploring and testing therapies that destroy one cell at a time by targeting a protein found abundantly on the surface of PCa cells. That protein is called prostate-specific membrane antigen (PSMA). It is different from PSA (prostate specific antigen) because it is contained surface-to-surface within the cell’s membrane, rather than on its surface. Thus, it is considered a transmembrane protein. It has a unique structure with activity that can help cancer. Chang (2004)^[i] compares PSA vs PSMA:

PSA	PSMA
Secretory protein Known function—liquefaction of semen Measured in serum [blood] as a cancer marker Decreased with androgen deprivation	Integral membrane protein Several enzymatic functions Upregulated with androgen deprivation RT/PCR used to detect in serum; not verified as a screening tool/marker Expression correlates with cancer aggressiveness and represents an indicator of poor prognosis

Thus, PSA is a useful tracker of PCa because it generally (but not always) rises as tumors grow in size and develop greater aggression, and it drops when treatment is effective; in PCa that has advanced beyond the prostate capsule, hormone treatment that deprives the tumor of testosterone has the effect of putting the brakes on PCa, so PSA falls until the cancer cells outsmart the androgen deprivation. On the other hand, PSMA plays in role in fostering PCa growth and development, and it actually rises during androgen deprivation.

Strategy: target PSMA to cut off PCa supply lines

Thanks to molecular biology research by Kaitannis et al. (2017), we now know that PSMA indirectly activates a cancer-causing pathway involving the PI3K protein kinase.^[ii] This triggers a specific molecular signaling pathway that regulates normal cell processes required for the cell to thrive; when hijacked by cancer, this pathway promotes the survival and proliferation of tumor cells in many human cancers.^[iii]

A novel therapeutic strategy is to target PSMA in a cancer cell’s membrane so as to disable it. If this prevents the signaling pathway, it basically dooms the cell so it fails to survive. If there were a way to make this one-by-one approach efficient, eventually PCa tumors would simply die off. The resulting reduction in disease volume could be tracked by PSA blood tests; as the cancer cells become inactive, the tumor burden shrinks, and the PSA begins to drop.

The RESIST-PC Phase II trial

In early 2017, a clinical trial was launched to test the use of lutetium-177 (Lu177), a radioactive isotope of the chemical element lutetium, in patients with mCRPC. The trial was called Lutetium-177 (Lu177) Prostate-Specific Antigen (PSMA)-Directed EndoRadiotherapy (RESIST-PC).^[iv]

Here’s how it works: There are molecules that are very appealing to the PSMA receptors in the cancer cell’s membrane, and the receptors will attach the molecules to themselves. These molecules can be “labeled” or bound with a radioactive isotope—in this case, Lu177. Then the molecule acts as a transport vehicle with lethal cargo. It is not dangerous during travel, but once the molecule attaches to the cancer cell, the physical contact allows the exposure to the isotope’s radiation gradually destroy each PCa cell to which it is attached without undue harm to neighboring healthy cells.

Preliminary results of the RESIST-PC trial were presented at the 2019 American Urological Association meeting (Chicago). 64 patients with mCRPC had been treated, and Lu177 was found to be “…well tolerated, and PSA declined by 50% or greater in 38% of patients,” and the best response was linked with three cycles of treatment.^[v] The response time varied from 6-49 weeks (average 22 weeks). There were side effects such as nausea, vomiting, bowel disorders, etc. but most were reported to be mild and self-resolving.

Much more research is needed before PSMA-targeted treatment with Lu177 or other isotopes can be made available outside of a clinical trial. However, this approach to treating incurable PCa is a great reason for optimism. Perhaps the day will come sooner than we imagine when we can announce a final victory over prostate and other cancers.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

[i] Chang S. Overview of prostate-specific membrane antigen. Rev Urol. 2004; 6(Suppl 10): S13–S18.
[ii] Kaittanis C, Andreou C, Hieronymus H, Mao N et al. Correction: Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors. J Exp Med. 2018 Jan 2;215(1):159-175.
[iii] https://www.biooncology.com/pathways/cancer-tumor-targets/pi3k.html
[iv] https://clinicaltrials.gov/ct2/show/NCT03042312
[v] Schieszer, J. “PSMA-targeted therapy well tolerated in men with mCRPC.” Urology Times, Jan. 20, 2020. https://www.urologytimes.com/genitourinary-cancers/psma-targeted-therapy-well-tolerated-men-mcrpc