Phillip S. Low, PhD, Provides In-Depth View of 177Lu-PSMA-617 Development for Metastatic CRPC

Phillip S. Low, PhD, Presidential Scholar for Drug Discovery and Ralph C. Corley Distinguished Professor of Chemistry - Biochemistry at Purdue University in Lafayette, Indiana

The FDA recently approved ¹⁷⁷Lu-PSMA-617 (Pluvicto) for patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC) who have previously been treated with an androgen-receptor pathway inhibitor and taxane-based chemotherapy.¹ This is one of few therapies approved for this indication, and the first approved targeted radioligand therapy in this setting.

This treatment is unique in that it is injected into the bloodstream, binds to target cells that express PSMA, and damages the target and nearby cells thereby stopping them from replicating or triggering cell death. The approval was based on results of the phase 3 VISION trial (NCT03511664) which examined use of the agent plus standard of care (SOC) vs SOC alone in the indicated patient population.

Phillip S. Low, PhD, Presidential Scholar for Drug Discovery and Ralph C. Corley Distinguished Professor of Chemistry - Biochemistry at Purdue University in Lafayette, Indiana, led research that was critical to the development of this agent. His research was similarly instrumental to the development of pafolacianine (Cytalux), which was approved in November 2021 as an imaging drug to detect ovarian cancer lesions during surgery.²

“Before therapy and after injection into the vein, this molecule homes in very specifically to the malignant cells, avoiding uptake by adjacent healthy cells, and concentrates the radioactivity to the cancer tissue. You don’t have the problem of trying to find and locate all of these small malignant lesions, that would not be easily visualized by imaging techniques that would allow you to focus the external beam on that particular radioactive lesion,” said Low.

In an interview with CancerNetwork®, Low spoke about the development of this drug, how it’s unique, and what the next steps are for developing treatments in this patient population.

Can you discuss how development of ¹⁷⁷Lu-PSMA-617 began?

Our interest in developing targeted medicines began when we were working on delivering drugs to cancers that overexpress a folate receptor. We found that we could use the vitamin folic acid to carry and attach drugs to cancers that have an enormous appetite for this vitamin. Folic acid turns out to be a very important vitamin for cancer cell growth because it’s required for the synthesis of DNA. We achieved significant success in using folate to pool cancer cells into gobbling up many different drugs that were attached to folate, and that worked very well.

We’ve had [pafolacianine] recently approved by the FDA that exploits this greed that cancer cells have for folic acid. We were on the lookout for other molecules that cancer cells might want to grab and internalize aggressively. We found that PSMA was a protein that was expressed on prostate cancers, but not very significantly expressed on any other cell types. We decided to try to exploit this protein to see if we could use it to deliver drugs very selectively into cancer cells.

When the atomic structure of PSMA was published, we jumped on it immediately and used the 3-dimensional structure of the protein to design a small molecule that would fit down into a very specific pocket on the surface of PSMA. We then used that molecule to carry and attach imaging agents and therapeutic agents with a number of different detached molecules and used it to ferry attached drugs into prostate cancer cells.

The one that turned out to be the most successful in this delivery was lutetium 177, the radionuclide. If captured by a cancer cell, it will sit there and shoot bullets in all directions and the radioactivity will kill the cancer tissue without significantly damaging the adjacent healthy tissue. That is the basis of the efficacy or the therapeutic benefit from this targeted therapy. It concentrates the radioactivity in the prostate cancer and avoids retention and accumulation of the radioactivity in healthy tissues. You are able to selectively irradiate just cancer tissue with this approach. It was inspired by success with a different tumor-specific homing molecule that would carry other attached drugs to cancers that overexpress the folate receptor. We used the overexpression of PSMA on prostate cancer cells to deliver radiotherapies specifically to the prostate cancer tissue.

What do you think makes the mechanism of action unique in this agent?

It’s unique for a couple of different reasons. First, most radiotherapies to date are based on an external beam where you basically shine a radioactivity beam. To say it in the vernacular, very specifically on the cancer tissue. This has advantages in that it’s very specific; you can focus that beam very selectively, but it has many disadvantages and these include the fact that the beam will also hit tissue on the sides of the cancer mass and will extend on through and damage cells on the far side of the malignant tissue.

In addition to that, one must know exactly where the malignant lesion is located. Otherwise, you don’t know where to shine the beam. It often is useful for reducing the sizes of very large tumors, but if you can’t see and locate these smaller metastatic lesions, you don’t knock those out. If you look at the images of the patients that have been treated with this [agent] before and after therapy, you will see that in some cases there are several hundred very small lesions spread throughout the body. Before therapy and after injection into the vein, this molecule homes in very specifically to the malignant cells, avoiding uptake by adjacent healthy cells, and concentrates the radioactivity just in the cancer tissue. You don’t have the problem of trying to find and locate all these small malignant lesions that would not be easily visualized by imaging techniques that would allow you to focus the external beam on that particular radioactive lesion.

Many patients [may] had up to 900 different lesions, and its numerically difficult to find and shine the beam very selectively on all of those. Whereas [with] a single injection into the vein, that injected radioactivity, very specifically to the cancer tissue, allows you to reach and treat all these malignant metastatic lesions everywhere in the body. It has many advantages over other areas of radiotherapy. In fact, I think this is only about the second major targeted radiopharmaceutical to be approved by the FDA.

What are the next steps for researching this drug in this patient population?

There are 2 directions that the clinical research can go. One is to move this therapy to earlier and earlier stages of prostate cancer. Right now, it’s only approved for metastatic castration-resistant prostate cancer, and this is really the end stage of the disease. [By this time] the cancer has mutated significantly so that it’s become much more difficult to kill and to eradicate. If we move to earlier stages of the disease, before the cancer has had a chance to develop all these resistance mutations, this will be much more effective or at least it’s anticipated to be; we’ll have to wait and see. If that proves to be the case, the benefit to the patient will be even greater. The other direction is of course, although prostate cancer is the major cancer that over expresses PSMA, in the several other cancers that express high levels of PSMA, and it will be important to go after and demonstrate the benefit of using this approach in other cancers also.

What other projects are you currently working on?

The phase 3 data [of using pafolacianine in lung cancer] are completed. I’m not privileged to announce them, but they’re terrific. What we’re working on [in the lab] is relevant to the current PSMA-targeted radiotherapy, we’re encouraged to go after other tumor-specific targeting ligands and develop [treatment for them]. We’re working on developing targeted radiotherapies for many other cancers right now. We can’t predict what’s going to work and what’s not going to work, but I anticipate that several of these [therapies] that we’re currently working on will be very effective. We have excellent results in animal models, and the next step is to take them into humans, but we haven’t done that yet.

References

1. Novartis Pluvicto approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer. News Release. Novartis. March 23, 2022. Accessed March 29, 2022. https://bit.ly/3iHcJGN
2. FDA approves new imaging drug to help identify ovarian cancer lesions. News Release. FDA. November 29, 2021. Accessed March 29, 2022. https://bit.ly/3qJCUB2