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A Publication of the Patrick C. Walsh Prostate Cancer Research Fund

 


Special Delivery to Metastatic Prostate Cancer: PSMA-Targeted Poison

This protoxin is a copycat killer: like immune cells, it pokes lethal holes in cancer cells.

Date: 11/05/2019

Special Delivery to Metastatic Prostate Cancer: PSMA-Targeted Poison
Brennen, Denmeade, and Isaacs: Protoxin mimics the way immune cells kill cancer.

When all goes well, the body’s immune cells should recognize prostate cancer as something bad that shouldn’t be there, and then attack the cancer. In effect, they should stab it to death – poking holes in the cancer cells’ surface. Unfortunately, for a variety of reasons, so far prostate cancer has proven to be resistant to immunotherapy.

So how can we get to metastatic prostate cancer cells to kill them? Scientist John Isaacs, Ph.D., working with colleagues Nathaniel Brennen, Ph.D., Emmanuel Akinboye, Ph.D., and Samuel Denmeade, M.D., has come up with a solution: special delivery. The “package” to be delivered is chimeric protoxin, a deadly (to cancer!) chemical weapon that’s the next best thing to having an army of cancer-killing immune cells. “It short-circuits the lack of immune cells by mimicking the way these cells kill cancer,” says Isaacs. This protoxin, in other words, is a copycat killer: like immune cells, it pokes lethal holes in cancer cells. What really matters, Isaacs adds, are the holes – not the hole-punchers. “It comes down to whether enough holes are produced to kill the cancer cells. Our approach doesn’t require the immune cells themselves.”

To put the “address” on the package – to make sure it goes only to the right cells, and doesn’t harm normal cells – Isaacs and colleagues made it prostate-specific. Even though metastatic cancer cells have spread far from the prostate, they still have PSMA (prostate-specific membrane antigen), a molecule that sits on their surface. The PSMA is the address. Metastatic prostate cancer cells also still make PSA, and here, the PSA acts as the detonator for the protoxin.

“Both PSMA and PSA function as molecular scissors, capable of cutting proteins at specific sites,” explains Isaacs. Using protein engineering, the scientists fused the cancer-killing poison to serum albumin (a protein made by the liver and carried in the blood), “to keep this chimeric protoxin from binding to normal cells throughout the body, and to increase delivery to the tumor,” when the drug is administered systemically via the bloodstream. This protein is engineered to require cutting by PSA to activate the cell-killing pore forming (hole-poking) ability of the liberated bacterial toxin.”

In elegant work, Isaacs and colleagues modified the protoxin so that when it is out for delivery – when it’s circulating in the blood – it is inactive, and harmless. But when it reaches cells that have PSMA, watch out! “It selectively binds to the surface of metastatic prostate cancer cells that express PSMA, and this binding enables PSA to activate the protoxin by acting as a molecular scissor,” Isaacs says. In other words, the mail bomb only goes off when PSA snips open the package. “We are accumulating the preclinical validation needed for clinical development of this PSMA-targeted chimeric protoxin activated by PSA.”