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Targeting PSMA: Amazing Potential (Part 1)
In December, 2020, the FDA approved 68Ga-PSMA-11 PET, a new type of imaging scan that can be used to find very small amounts of prostate cancer in the body. The work of PCF-funded investigators including Neil Bander, M.D., laid the foundation of efforts to specifically target prostate cancer cells. In this 4-part series, Janet Farrar Worthington follows the 25-year journey.

Nearly three decades ago, Neil Bander, M.D., now Director of Urological Oncology Research at Weill Cornell, saw the potential of a newly discovered molecule called PSMA to be used in two ways:  for imaging and also for precisely targeted treatment of prostate cancer.  Over the last few years, both aspects of his vision have been coming true – in clinical trials and newly in practice in the U.S., and in practice in Europe, Australia, South Africa and elsewhere – for a growing number of men with prostate cancer.

You’re going to be hearing a lot more about PSMA, and about strategies for targeting it.  (In case you haven’t heard, prostate-specific membrane antigen, PSMA, is a protein present on the cell surface of prostate cancer cells).  This promising new strategy is based on an antibody developed by Bander and colleagues, and it is no exaggeration to say that without PCF funding, this game-changing approach wouldn’t be nearly as far along in development, testing, and use in clinical settings as it is today.   Briefly, here’s how it came to be:

HOW WAS PSMA DISCOVERED?

The late 1980s-early 1990s saw the dawn of monoclonal antibodies, lab-developed clones of B cells which produce antibodies designed to zero in on one specific molecular target, like molecular homing pigeons.  Scientists studying cancer were using this technology like gangbusters, “trying to find tumor-specific antigens on cancer cells that could be a way to distinguish cancer cells from normal cells at the molecular level,” says Bander.  (An antigen is often a foreign substance, like a toxin, bacteria, or mutated cancer protein; when the body detects it, the immune system makes a very specific antibody to identify and target this intruder.)  The hope, if they could find a way to target just cancer, and not normal cells, was to develop more precise treatments – unlike systemic chemotherapy, which takes a toll on the rest of the body.

In 1987, a urologist named Gerald Murphy, M.D., D.Sc., who directed the Roswell Park Memorial Institute for cancer research and treatment – and who developed the original PSA test –made a monoclonal antibody, called 7E11.  “Not much happened with that antibody until 1993, when a group at Memorial Sloan Kettering Cancer Center, headed by Skip Heston, Ph.D., used Murphy’s antibody as a reagent or tool to clone the gene for the antigen that was detected by the antibody,” says Bander.  “When they cloned the gene, their analysis indicated that it was very specific for prostate cancer.  They also found it was present in the cell membrane of prostate cancer cells,” and so they named it “prostate-specific membrane antigen” or PSMA.

PCF STEPS IN TO FUND THIS PROMISING WORK

Soon afterward, Bander received PCF funding to develop antibodies that were specific to prostate cancer cells.  He studied 7E11, and realized that “if you were looking to target PSMA in patients, this antibody had a significant flaw:  it binds to a part of the PSMA protein that is inside of the cell membrane, a site that antibodies can’t readily reach.  In fact, the 7E11 antibody could only bind to dead prostate cancer cells, a case where the cell membrane had been disrupted. But, fortunately, the PSMA molecule spans the cell membrane with a short region of it inside the cell (where 7E11 binds), another region traverses the membrane, and the largest part of the molecule is sitting on the outside of the cell.  “If you want to have an antibody that can bind to the tumor cell in patients, that antibody really needs to be directed to the part of the molecule that’s on the exterior of the cell.”  Because the antibody is administered through the bloodstream, he continues, “the only thing the antibody sees is what’s on the outside of the cell.  We set out to make a series of antibodies to the part of the molecule that’s on the outside of the cell.  A few other groups, including Skip Heston’s group, also set out to do the same thing.  We happened to get there first.”

In 1997, Bander and colleagues published in Cancer Research their development of four antibodies, the first antibodies that could bind the part of PSMA on the exterior of the cell and the 1st antibodies that could bind living prostate cancer cells.  Their lead antibody was called J591.  Over the next few years, also with PCF funding, “we did a pretty thorough analysis of these antibodies – where they bound on PSMA and how specific they were for prostate cancer cells vs. normal tissues.”  They discovered that J591 could bind to living cells, “which the 7E11 antibody did not do.”  Then, “because our goal from the outset was to develop this into a therapeutic,” they “humanized” the antibody, genetically re-engineering it from a mouse-derived antibody into a sequence that the human body would not see as a foreign protein.

EVEN MORE PROMISE ON THE HORIZON

Researchers spent years “really trying to understand more about PSMA, how good a target it was.” “We learned that PSMA was very highly overexpressed in prostate cancer.”  Although normal prostate cells are also PSMA-positive, prostate cancer cells are PSMA-loaded.  “We also found that as prostate cancer cells get more aggressive and are more likely to kill a patient, they have more and more PSMA on them.  The more dangerous the prostate cancer is, generally speaking, the more PSMA there is.”

And, they found, the amount of PSMA on the cell surface is affected by male hormones (androgens).  “When you put a patient on hormonal therapy (androgen deprivation therapy, ADT) you actually increase the amount of PSMA on the cell surface by 5-10-fold; you find enormous amounts of PSMA sitting on the surface of prostate cancer cells.” This is a really fortuitous finding because ADT is the cornerstone of treatment for advanced prostate cancer and it increases the density of PSMA on the tumor cell surface. This is the equivalent of significantly increasing the size of the bullseye on a target. In effect, it’s the metaphorical equivalent of increasing the diameter of a golf hole to more than 3 feet wide (!); it certainly changes the game.

But wait!  There’s more!  Bander’s team looked at other types of cancers, and found that the blood supply in almost every other type of solid tumor was PSMA-positive!   For example, a kidney tumor itself does not make PSMA – but its blood supply sure does.  In fact, “the blood supply is pretty strongly PSMA-positive.  We were surprised by this, but the finding was also independently and simultaneously noted by the Heston group.  We did not and still do not understand why that is the case, but this means a PSMA-targeted drug is potentially useful not just in prostate cancer, but in other types of cancer, where the approach could be to basically eliminate the blood supply to the tumor.  We’ve done some clinical trials that show this is a real possibility.”

One more early finding, something “we didn’t anticipate,” says Bander:  “When the antibody binds to PSMA on a living prostate cancer cell, that cell swallows the PSMA antibody and anything that’s attached to it!”  This discovery, he continues, “opened up the door to develop antibody-drug conjugates: you put a very potent drug on the antibody, direct it specifically to the prostate cancer cells, and the prostate cancer cell swallows up the drug, whereas PSMA-negative cells don’t.  This was, in effect, a door opening to developing chemotherapeutic agents that are only taken up by the cancer cells.”

The door keeps opening wider.  “If you look at PubMed today,” says medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of PCF, “there are now 3,707 research papers on PSMA discoveries.  That’s a paradigm changing impact– and PCF ‘first in field’ funded the early discoveries that opened the entire field of therapeutics and imaging!”

Next:  Part Two: Making it Happen

Janet Worthington
Janet Farrar Worthington is an award-winning science writer and has written and edited numerous health publications and contributed to several other medical books. In addition to writing on medicine, Janet also writes about her family, her former life on a farm in Virginia, her desire to own more chickens, and whichever dog is eyeing the dinner dish.

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