×

Get the updated Prostate Cancer Patient Guide 2021 Edition, available as a free emailed pdf.

Go here to learn more or to get a mailed copy.

Targeting PSMA: Dramatic Success (Part 3)
This 4-part series follows the science on PSMA – a key protein on prostate cancer cells.  Decades ago, PCF began funding research into this approach to imaging and treating prostate cancer.  Those efforts have paid off: in the last 6 months PSMA has been in the spotlight, garnering 2 FDA approvals and multiple publications.

PCF-funded investigator Neil Bander, M.D., Director of Urological Oncology Research at Weill Cornell and a pioneer in the study of PSMA (prostate-specific membrane antigen), developed an antibody that targets this molecule that sits on the surface of prostate cancer cells.  He later characterized PSMA, and found many reasons why it is an excellent way to target prostate cancer.  Results from work by Bander and others generated worldwide interest – particularly in Germany.

IN SELECT PATIENTS, RESULTS ARE ENCOURAGING

Terms to Know: Ligands, Antibodies, and Radioisotopes PSMA-targeting ligands and antibodies are two different types of molecules.  Anti-PSMA antibodies are proteins, and are larger; PSMA-targeting ligands are chemicals, referred to generally as “small molecules.” They are different approaches to target and bind to PSMA, and each has its own advantages and disadvantages.  The FDA has approved 2 imaging agents using PSMA-targeting ligands. The ligand or antibody binding to PSMA can be used to deliver a payload, such as a radioisotope, to the prostate cancer cell.  Radioisotopes are chemical elements that release radioactive particles.  After the radioisotope enters the cancer cell, these high-energy particles can destroy the cancer by damaging its DNA.  Different elements release different types of particles, such as alpha or beta, that behave in certain ways in the body.  The treatment used in the VISION trial, Lu177, releases beta particles.

Bander made an antibody that targets PSMA and linked it to a radioisotope called lutetium-177 (Lu177), a beta emitter.  With colleagues at Weill-Cornell, and with a nod from the FDA, in 2000, they began a series of prospectively designed clinical trials that showed excellent targeting of metastatic prostate cancers wherever the disease was located in the body.  These treatments resulted in PSA declines and improvement of pain. At the time, however, the pharmaceutical industry was not interested in radioactive drugs and the prostate cancer field was more focused on the development of Taxotere chemotherapy.

In Germany, around 2013, physicians began using different agents, small molecules called ligands, instead of antibodies, that bind to PSMA.  Some of these had been developed in the U.S. by John Babich, Ph.D. (then at Molecular Insight, Inc, now at Weill-Cornell) and Martin Pomper, M.D., Ph.D. at Johns Hopkins.  The Germans tested Lu177 as well as a different radioisotope, actinium-225 (Ac225), an alpha emitter, says Bander.  “Ac225 is several thousand times more potent than Lu177.”  In Germany, a “compassionate use” program is frequently used to allow the use of new, previously untested therapies in patients who have exhausted all approved treatment options available.  This means that, for a patient with a serious illness who understands and agrees to take the risk, doctors can try promising – but unproven – treatments outside of a formally designed clinical trial.  “So, in Germany, they were able to give these radiolabeled ligands to patients on an ad hoc basis, not as part of a formally designed and specified treatment protocol.  A number of centers in Germany began to make their own radiolabeled-ligands.  They started treating patients and publishing the results, sometimes on just 1 or 2 patients, sometimes on small groups, sometimes on large retrospective series of patients,” in various nuclear medicine journals.

“The other thing they did,” Bander continues, “was, they would only treat patients whose cancers showed up well on PSMA-PET scans.  They selected their patients, which helped them achieve high response rates.”  A report of two patients treated with a PSMA ligand carrying Ac225, in particular, showed spectacular results.  “To say they were dramatic would be an understatement.  These two patients had already had their cancer progress despite treatment of every kind then available for prostate cancer.  Everyone was blown away by those two cases.”  The “before and after” images showed that widely metastatic cancer had completely disappeared.  PSAs that were in the hundreds in one case or thousands in the other, became undetectable.

Those ligands became readily available in Germany, Austria, Australia, India, South Africa, and “other countries that have more liberal regulatory policies than the U.S.,” Bander says.  “It generated an onslaught of publications, all showing excellent results.  That’s what really ‘flipped the switch’ and got Big Pharma interested; among them, Novartis and Bayer.”

This provided a backdrop that ultimately led to the recently reported (at ASCO 2021) phase 3 trial of the ligand PSMA 617-Lu177, run by Novartis, that confirmed a significant delay in tumor progression and improved survival in patients with metastatic castrate-resistant prostate cancer.

Coming next in Part 4: How researchers are working to maximize cancer-killing ability while minimizing side effects.
Previous: Read Part 2 here

Terms to Know: Ligands, Antibodies, and Radioisotopes PSMA-targeting ligands and antibodies are two different types of molecules.  Anti-PSMA antibodies are proteins, and are larger; PSMA-targeting ligands are chemicals, referred to generally as “small molecules.” They are different approaches to target and bind to PSMA, and each has its own advantages and disadvantages.  The FDA has approved 2 imaging agents using PSMA-targeting ligands. The ligand or antibody binding to PSMA can be used to deliver a payload, such as a radioisotope, to the prostate cancer cell.  Radioisotopes are chemical elements that release radioactive particles.  After the radioisotope enters the cancer cell, these high-energy particles can destroy the cancer by damaging its DNA.  Different elements release different types of particles, such as alpha or beta, that behave in certain ways in the body.  The treatment used in the VISION trial, Lu177, releases beta particles.
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.