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MRI’s Future Role in Prostate Cancer Treatment

Prostate MRI’s ability to show what’s happening in the prostate is already transforming how prostate biopsies are done.  Will it change treatment for prostate cancer, as well?

Radiologist Peter Choyke, M.D., believes it will.  He is Senior Investigator and Director of the National Cancer Institute’s Molecular Imaging Branch, and I recently interviewed him for the Prostate Cancer Foundation’s website.  He gave me some good examples of what MRI is already doing, and what’s on the horizon:

 Active surveillance:  “You can monitor patients on active surveillance with MRI,” says Choyke, but there’s a caveat:  “What you’ll typically see is not much change over two to three years.  But if you do biopsies over time, it’s not uncommon to see grade migrations, like Gleason 6 to Gleason 7, with no visible change on the MRI.”  Is that a significant change for the patient?  Does that mean that active surveillance has to stop and the man needs treatment right away?  “As far as I can see, there’s no right answer.  A lot of people are trying to substitute MRI for biopsies.  The danger there is that you will miss patients who are converting from Gleason 6 to 7.  Just because the MRI is unchanged doesn’t mean the histology (what’s happening within the cancer) is unchanged; that’s not a good assumption.”  Choyke suspects that MRI changes actually reflect growth of the tumor, “and are related to the number of cancer cells that are present – which is a really good index of how aggressive the tumor is.  If there are more cells, that’s a bad sign.  But if the cells are about the same in number, that’s not such a bad sign.”

One important role for MRI is before a man starts on active surveillance.  “You want an MRI to see what the extent of the disease is, to make sure you get a targeted biopsy of the lesion or lesions, and to make sure that you’re not putting someone on active surveillance who needs treatment instead.  By doing this, you get the patients who really should be on active surveillance, and can stay on it for much longer.”

 On the horizon:  Local treatment for prostate cancer:  MRI-guided treatments are being tested in clinical trials at the NIH and elsewhere.  The idea here is that MRI is getting so good, it may be able to provide a roadmap for treatment within the prostate.  Instead of removing or irradiating the entire gland, “we have a few protocols where we are trying to treat the lesions that we see on MRI.”  One approach is focal therapy, with MR-guided laser ablation “just to the lesion.”  If this works, there are some big advantages:  “We could significantly reduce the side effects from surgery and radiation,” says Choyke.  “We’re also very interested in, and are about to open enrollment for a trial of, local deposition of anti-androgen therapy – essentially putting androgen deprivation therapy (ADT) directly into the spot of cancer seen on the MRI – so the patient doesn’t have to undergo systemic ADT while receiving radiation therapy.”  Unlike, say, taking Bicalutimide by mouth, which affects the entire body, a micro-dose of Bicalutimide within the prostate tumor “only goes a certain distance before it’s washed away, and it’s in such a low concentration that the systemic effect is negligible.”   This will be tested in men with localized, intermediate-grade cancer, “where ADT is useful but not mandatory,” Choyke adds.  “There may come a time when this can be advanced to higher-grade tumors.”

Another trial in the works will test MR-targeted focal radiation.  “We’re very excited about this because with radiation, you can really do dose painting.  With a laser, you either kill or you don’t kill; you either burn it or you don’t burn it.  But with radiation, you can taper the dose around the edges of a tumor, where there’s a large expectation of cancer.  That’s good for the patient, because you’re not giving the same dose throughout and irradiating things that don’t need to be irradiated, like the rectum, urethra, or bladder base.”  This trial is “awaiting good planning software,” to help plot precisely where and how much the dose should be.

But much more testing is needed.  “First, do no harm.”  If it turns out that “we can treat the cancer successfully without a lot of side effects, that’s a good outcome.  All of that is enabled by the MRI providing the spatial information to direct these therapies.”

Artificial intelligence and MRI:  “We have a very good correlation between what’s on the MRI and the actual pathology of the radical prostatectomy specimen,” says Choyke.  “We have thousands of cases where we’ve compared the pathology to the MRI.  So now, with pretty good accuracy, we can predict the pathology from the MRI.”

But sometimes, MRI can’t see every bit of a tumor.  Sometimes normal tissue is interspersed with cancer, “at the resolution that MRI can’t detect; cancer is sort of hidden in all that normal tissue.”  Sometimes, tumors have stroma (noncancerous connective tissue cells), that masks the cancer cells.  And then there are some higher-grade tumors that simply don’t show up on MRI.  “In our studies, it’s 5 percent, but I’ve seen it as high as 15 percent of patients with intermediate or high-grade disease who have negative MRIs.  We’re looking to see whether artificial intelligence (AI) can pull out these lesions that the human eye can’t detect.”  No one knows why this is; under the microscope, “the pathology of those lesions doesn’t look that different.

“You’d think by now we would understand this very well,” but because the vast majority of tumors do show up on MRI, “it’s hard to accumulate enough cases to make bold statements about what’s going on.  We are continuing to look at it – so stand by for more information!”

This is part3 of 3 stories on MRI, MRI’s role in cancer screening, and MRI’s potential use in treatment.

In addition to the book, I have written much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

 

 

 

 

 

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PSMA-Targeted Treatment:  Why Side Effects Matter

This new form of treatment for metastatic prostate cancer is being used in Europe, Australia and elsewhere, and being tested in clinical trials in the U.S.  As part of my series on PSMA-targeting, here’s more of the story:

We have talked a lot about the amazing results in some men with metastatic prostate cancer of PSMA-targeting radionuclides, being used in Europe, Australia, and elsewhere, but still in clinical trials here in the U.S.  Now, I’m all for moving drugs right along, damn the torpedoes, and giving anyone who wants to take the risk a chance to beat a terrible disease.  But there’s a good reason that the U.S. is taking this cautiously:  because some of these PSMA-targeting treatments – not all – can harm the salivary glands and tear ducts.  When these treatments become FDA-approved in this country, I believe the side effects will not be so severe.  Scientists like Neil Bander and Martin Pomper are developing agents that have much milder side effects.

The whole time I’ve been writing about PSMA, I have been thinking of Nathan (I changed his name to protect his privacy), a remarkable, tough and courageous man I interviewed in 2018.  He is one of the pioneer patients of PSMA-targeting treatment.  I want to tell you his story now.

On a dark day in 2013, Nathan was diagnosed at age 57, with stage 4 prostate cancer that had spread to his lymph nodes, his spine and hip.   His cancer was very aggressive: Gleason 9.  The prognosis was grim, and Nathan had a choice to make:  do what his initial urologist suggested, start on androgen deprivation therapy (ADT), hope it works for a long time and wait until the cancer gets worse, or go into “high-gear mode.”  He chose option B.  “If I have an aggressive cancer, I want to deal with it aggressively.”

So, in addition to starting on ADT and an androgen receptor blocker, abiraterone (Zytiga), plus prednisone – a combination that is now FDA-approved, but was about five years ahead of its time in 2013 – Nathan underwent a radical prostatectomy.  The surgery did not cure him, but eliminating the primary tumor dealt the cancer a severe blow and bought him more time.  “The plan all along was, kick the can down the road until science can catch up,” he says.  He assembled a team of doctors who had the same philosophy.

Next, Nathan got radiation:  high-intensity radiation to the spots of cancer in his spine, followed by 40 radiation treatments over two months to his pelvis and prostate bed.  Despite a change to a different androgen receptor blocker, enzalutamide (Xtandi), his cancer picked up steam.   Soon, his PSA was doubling every three weeks.  A PET scan showed new metastases, including a big one in his elbow.  In 2016, Nathan learned about the PSMA-targeted radionuclide treatment being done in Heidelberg, Germany.  He talked to his oncologist, who expressed concern about the side effects.  Nathan decided to go to Heidelberg.

The most worrisome side effect of this treatment was damage to the salivary gland.  As it turns out, PSMA doesn’t quite live up to its name; it is not entirely “prostate-specific.”  This molecule normally exists in small amounts in the salivary glands and a few other places of the body.  The drugs that target the PSMA-containing cancer cells don’t know the difference, and they can kill or damage these normal cells, too; there is also a risk of kidney toxicity.  “The salivary gland problem happens right away,” Nathan says.  “But the treatment also works right away.  They give you an infusion and the cancer cells are dying within hours.”

Despite the risks and the unknowns, Nathan wanted to go ahead – sooner, rather than later.  “I knew they had done this treatment on no more than 30 to 40 patients.  But I also didn’t want to get to a point where I was going to be in bad shape,” before the cancer burden grew bigger and began causing pain, “and then get the treatment.”

Before he could undergo the treatment in Germany, Nathan had to have a PSMA-PET scan.  “My body lit up like a Christmas tree with PSMA-PET: it showed cancer in my ribs, sternum, manubrium, scapulas, upper extremities, femur, and numerous places on my spine.”

Nathan weighed the risks of side effects against the possibility of getting a true remission of his cancer.  The hope of remission won.

What’s it like?  The treatment itself is given by infusion and only takes 10 minutes – and in 10 minutes, prostate cancer cells throughout Nathan’s body started to die.  Before and after his treatment, he drank “tremendous amounts of electrolyte fluids,” to minimize the risk of kidney damage:  “The more you drink, the more you can flush out the radioactive materials.” Nathan was given ice packs to put around his neck to help protect the salivary glands.  He was supposed to use them for six hours; he kept icing his neck for 12 hours, and also drank as much water as he could.  “I think in those two days, I drank between 10 and 12 liters of electrolyte water.

“This treatment was only approved by the German government on a humanitarian basis,” he notes, “basically, to treat people in extensive pain, who were far along in the disease, and who didn’t have much time to live.”  Nathan was the only man on the ward who was not taking morphine.  “One guy came in in a wheelchair, in bad shape.  He got discharged before me.  He walked out – didn’t use the wheelchair.  That’s how quickly it alleviated his pain and was killing the cancer cells.”  The man in the next room had an exceptional response, as well:  “He was from the Netherlands.  He told me he came in when his PSA was 964, got his first treatment, and his PSA went down to 11, then his second treatment was two months later, and his PSA was down to 3.5, and now he was there for his third treatment.”

Two weeks later, when Nathan went to see his oncologist back in New York, his PSA was undetectable.  A second treatment was scheduled.  “I was already experiencing significant salivary gland problems,” Nathan says, “and we thought he might reduce the dosage.”  However, he doesn’t know whether the dosage was reduced for the second round.

Going Off Enzalutamide

Enzalutamide may have helped make the treatment more effective:  some studies have suggested that enzalutamide enhances PSMA.  Otherwise, Nathan wasn’t sure how helpful it was.  Six months after his second treatment in Germany, he asked his doctor: “What do you think about me getting off enzalutamide, and staying on Lupron?  He said, ‘I don’t know if it ever really worked on you; it only lowered the PSA for a few weeks.’”  So Nathan tapered off, then stopped taking it altogether – which led him to another milestone:  “I said, ‘So, am I still castrate-resistant?”  His doctor told him, “’From a scientific standpoint, once you’re castrate-resistant, that’s it.  They don’t change that.’  But I don’t think they’ve ever come across a situation where people start dialing back their medicines.”

“Not for the Faint of Heart”

About a year after the treatment in Germany, Nathan got a PET scan.  “There was no evidence of cancer, which is great news,” he says.  However, “they said I had a compression fracture in my spine.”  Previously, when he had the high-dose radiation to his spine, he asked about side effects.  The radiation oncologist told him, “In rare cases, people can get compression fractures.  Don’t jump out of any planes.”  But back then, this was a new treatment, and there was no long-term follow-up.  To treat the fracture, he underwent a procedure called kyphoplasty, done by an interventional radiologist.  It involves a balloon – like angioplasty – that restores space in the collapsed vertebra, which then is filled in with glue and cement to restore the bone and relieve pain.

In 2018, Nathan got another PSMA-PET scan at Weill Cornell.  “Thankfully, I was PSMA negative.”  But Nathan cautions that the radionuclide treatment he received is “not for the faint of heart.”  The loss of salivary gland function “has not been pleasant.  It encompasses many things.  I can swallow, and I can taste, but I get a tremendous amount of dry mouth.”  A CT scan showed esophagitis – inflammation of his esophagus from lack of salivation, and thyroiditis.  “I have to constantly keep lubrication going.  It has gotten slightly better, and they told me it’s possible that if the treatment didn’t burn off all my salivary glands and there were some cells left, they could possibly regenerate, but it would take a long time.   I think I’ve gotten about 20 percent back over the two years.”  Nathan uses gels in his mouth every night.  “Otherwise, I wake up choking.”  He also uses prescription toothpaste and extra fluoride to protect the enamel on his teeth.

He is trying to limit scans that will subject his body to more radiation (MRI, for example, has no radiation; CT does).  “Over the last couple months, my creatine level (reflecting kidney function) has slowly increased.   It’s not out of the range of normal, but at the high end.  I’m conscious that these radioligand therapies can produce kidney damage.”

“It’s an amazing age we’re living in,” Nathan says.  “I’m happy to be here, grateful that I was able to kick the can long enough to have gotten this treatment.”  Whenever he sees his oncologist, the conversation ends with the doctor saying, “Grow old.”  And Nathan says:  “I plan to.”

Note:  If you are seeing this as a solo story, click here for more.

 

In addition to the book, I have written much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

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PSMA-Targeting Radionuclides:  Serious Side Effects, and Navigating a Safe Course

This new form of treatment for metastatic prostate cancer is being used in Europe, Australia and elsewhere, and being tested in clinical trials in the U.S.  As part of my series on PSMA-targeting, here’s more of the story:

With the dramatic results in some men, why aren’t radionuclides a done deal here in the U.S?  Because – just like the use of magic in fairy tales – they come with a price.

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.  The alpha particle radioligands (using the small molecule delivery system) target the salivary glands, where a small amount of PSMA is made.  Beta particles such as Lu177, used in the Novartis compound, generally cause only minor salivary gland toxicity, Bander says.  But “since alpha particles are at least 1,000 times more potent than beta particles, when you put the alpha particle on the ligand, it targets the salivary glands and the tear glands, and they get destroyed.”

Now, you might be thinking, losing my salivary glands is a small price to pay for really knocking back and maybe even curing my prostate cancer.  But Bander would suggest that you think very carefully about this.  “When you destroy the salivary glands, the result is absence of saliva, inability to taste, difficulty swallowing, and tooth decay and loss.  Affected patients report that it’s a pretty miserable existence.  So that has proven to be a major impediment to using the small ligands to target the alpha particles.  Despite some amazing responses with the alpha particle, “it can be intolerable for the patient.”

So:  Is there any way to protect the salivary gland?  As it turns out, there is.  “While the small molecule ligand targets the salivary glands and lachrymal glands, antibodies do not,” says Bander.  “Antibodies are much larger molecules than the ligands.”  With the small ligands, the radioisotope “can easily pass through normal tissue barriers.  But when we deliver the radioisotope by use of the antibody, we see no targeting of the salivary or lachrymal glands.”

In fact, “we recently completed a trial at Weill Cornell using our J591 antibody to target the alpha particle, Ac225.  Based on an interim analysis, we have seen minor salivary gland toxicity in six of 27 patients, five of whom previously had been treated with the small ligand.  We found that the antibody-targeted alpha particle was well tolerated and very effective against the prostate cancer, even in patients who previously had progressed after treatment with the ligand Lu177.”  This Phase 1 trial was funded by the Prostate Cancer Foundation.

Another key difference between the antibody and ligand: “The ligand is excreted from the body through the kidney and bladder,” says Bander, and there is a risk of kidney toxicity.  “It has not yet been a significant problem, although there have been a few reports of kidney toxicity from the ligand with an alpha particle on it, and it may take a while to develop.  With the antibody, the path of excretion is through the liver, so the kidney is less likely to be subject to damage from the alpha particle.  The liver is pretty resistant to radiation.”

So… no to the ligands, then?  Not so fast, says Bander.  “Here at Cornell, we have data that suggests the best way to target prostate cancer is actually using a dual-targeted combination of the antibody and the ligand.  Our data show that with the combination, we can deliver a substantially higher dose to the tumor without increasing side effects.”  That’s because these agents each behave differently in the body.  “Dual targeting also allows us to use both the beta and the alpha emitters simultaneously, and our research shows this combination of alpha and beta isotopes to be very complementary.  Ultimately, the dual-targeting approach, with both antibody and small ligand, provides a substantial increase in the dose to the tumor without additive toxicity.  At Cornell, we are beginning to treat mCRPC patients with the ligand-Lu177 plus the antibody-Ac225.  Our laboratory data and our understanding of the biology of how these agents interact suggest a substantial benefit to this dual targeting/dual isotope approach.  The ability to substantially increase the dose to the tumor offers, I think, significant potential benefit for improved survival.”

This is what Bander envisioned 30 years ago, when he first began investigating PSMA.  And, he says, “it’s going to get a lot better.”   At the 2019 ASCO international oncology meeting, a session on PSMA “filled a 4,000-seat auditorium.  I was joking that a few years ago, we could have had that meeting in my hotel room and there would have been room for housekeeping!  It’s just like somebody flipped a switch.  Leveraging the ability to target PSMA for imaging and treatment is in the process of dramatically changing everything about how we approach prostate cancer – how patients are diagnosed, how they’re monitored, and how they’re treated.  If serial PSMA imaging can be shown to reflect tumor response, it has the potential to be used in the development of all prostate cancer drugs going forward to provide rapid insight into drug efficacy.  That will make new drug development in this disease much more rapid and efficient.  It’s a game-changer.  I’m confident that the best is yet to come.”

Note: If you are seeing this as a solo story, click here for more.

 

In addition to the book, I have written much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

 

 

 

 

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PSMA-Targeting Radionuclides:  Dramatic Success

This new form of treatment for metastatic prostate cancer is being used in Europe, Australia and elsewhere, and being tested in clinical trials in the U.S.  As part of my series on PSMA-targeting, here’s more of the story:

As we have discussed here, 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.

Bander made an antibody that targets PSMA, and linked it to a radioisotope called lutetium 177 (Lu 177), a beta emitter.  With colleagues at Weill Cornell and “with a nod from the FDA,” in 2000, Bander 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 d eclines and improvement of pain.”  At the time, however, he notes, 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 that bind to PSMA: small molecules, called ligands, instead of antibodies.  Some of these had been developed in the U.S. by John Babich, Ph.D., (now at Weill-Cornell), and Martin Pomper, M.D., Ph.D., of Johns Hopkins.  The Germans tested Lu177 as well as a different radioisotope, actinium 225 (Ac225), “which is an alpha emitter,” says Bander.  “Ac225 is several thousand times more potent than Lu 177,” which, again, is a beta-emitting particle.  (I have to be honest here, I don’t fully understand alpha vs. beta particles, but this article might help those who are motivated understand more.)

In Germany, a “compassionate use” program is often used to allow the use of new, previously untested therapies in patients who don’t have much other hope.  This means that, for a patient with a serious illness who has no other medical options and who 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 (small-molecule radionuclides) to patients on an ad hoc basis, not as part of a formally designed and specified treatment protocol.  A number of centers in Germany started to make their own radiolabeled ligands.  They started treating patients and started publishing the results, sometimes on just one or two 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.”  Notably, a report of two patients treated with a PSMA-Ac225 ligand 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 of therapy then available for prostate cancer.   Everyone was blown away by those two cases.”  The “before and after” images showed that widely metastatic cancer had melted away from the pelvis, ribs, spine, liver and brain.  PSAs that were in the hundreds in one man, and 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 was just 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.”

At the June 2021 meeting of the American Society of Clinical Oncology (ASCO), results from the Phase 3 trial of LuPSMA (Lu177), run by Novartis, confirmed a significant delay in tumor progression and improved survival in men with metastatic castrate-resistant prostate cancer.

Note:  If you are seeing this as a solo story, click here for more.

 

In addition to the book, I have written much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

 

 

 

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Backstory: The Road to PSMA-Targeting Radionuclides

This new form of treatment for metastatic prostate cancer is being used in Europe, Australia and elsewhere, and being tested in clinical trials in the U.S.  As part of my series on PSMA-targeting, here’s more of the story:

Neil Bander, M.D., Director of Urological Oncology Research at Weill Cornell and a pioneer in the study of PSMA, saw the potential of targeting PSMA, a molecule that sits on the surface of prostate cancer cells, soon after it was discovered more than 30 years ago.  His research shed light on why PSMA was such a promising target, and in 2000 his team began clinical trials with J591, a PSMA-targeting antibody he made.

“We were interested in two different approaches,” Bander says.  “One was putting a radioactive isotope on the antibody” – a molecular grenade of cancer-killing radiation – “and the other was putting a drug on the antibody.”  This “antibody-drug conjugate” approach was very new; fewer than a handful of drugs were available to attach to antibodies, “and all of them were owned by drug companies.  We didn’t have ready access to those,” so instead, Bander’s team focused on linking a “radioactive payload” to the antibody.

 The other benefit of using a radioactive isotope as a weapon:  it could be seen on imaging!  “Because of the radioactivity, we could see where this antibody-isotope was actually going,” says Bander.

Think of an old movie, where as a B-52 plane travels, it’s superimposed on a map, and an arrow connects Point A – California, let’s say – to Point B – Guam on our plane’s journey – and all points in between.  Bander didn’t have an arrow, but he could plot the progress of the radioactive isotope just the same.  “We could see immediately that the antibody was going right to the tumor cells.  Wherever we saw tumor sites – on the patient’s bone scan, CT scan, or MRI – we could see those sites lighting up after we gave the radioactive antibody.  So right from day one, we knew we were hitting the target!  We knew we were actually delivering the radioactivity to the tumor sites.”

But Bander and colleagues noticed something odd:  the radioactive isotope was also going to other sites where there was no apparent cancer.  They soon realized what was happening:  the PSMA-targeting isotope was finding cancer that was too small to show up on conventional imaging!  “We knew very early on that this could potentially be a very potent imaging modality.”

The Phase One trials were for men with metastatic castrate-resistant prostate cancer (CRPC).  These were men whose cancer had progressed despite all the standard treatments of the day.  In about 10 to 20 percent of participants, “we did not see their tumors light up.”  Is this because their tumors somehow don’t make PSMA?  Bander doesn’t think so.  (Note: Martin Pomper of Johns Hopkins does, and is working on ways to target those non-PSMA-making cells.)  “If you remove prostate cancer, say in surgery or biopsy, and do a test to see if there’s PSMA – and this has been done in many thousands of patients – almost 95 percent are PSMA-positive.”  Nonetheless, in some men, the PSMA-targeting agent does not show up much on imaging.  “In our studies, we found about 15 percent did not image, and another 5 to 10 percent imaged weakly, but we treated all those patients anyway.  We found that if you are PSMA-negative or PSMA-weak, you are significantly less likely to have a good response to the treatment.”  However:  “If your imaging study lit up like a neon sign, you had a very high likelihood of responding.  It was a pretty clear distinction.”

Bander’s group tested two different isotopes and found that lutetium 177 (Lu 177) was the most effective.  “Responses varied, from no response to PSA stabilization to 95-percent decreases in PSA levels that could last many months,” says Bander.  “We also saw that as we increased the dose, the responses got better.”  Other centers reported success in some animal tumor models with breaking up the dose of radiation.  “Instead of giving just one big dose, if you split it up into two or more smaller doses, you could deliver an even higher cumulative dose.  So we did a phase 1 study of fractionated J591-Lu 177, gave higher doses and got better and more durable responses.”

This was 2007.  Why hasn’t this become mainstream therapy?  One big reason:  the pharmaceutical industry is like a freight train.  Once it gets going on a particular track, it picks up steam and generates huge momentum.  Until that happens, however, momentum can be very slow.  Twenty years ago, Bander says, “pharmaceutical companies had no interest in radiopharmaceuticals.”  Instead, their model was for literal shelf life: drugs put into a tablet or capsule and shipped to sit either at a pharmacy or in a patient’s medicine cabinet.  “Making drugs from living cells was a whole new area,” but the industry has evolved to “this greater willingness to make very complicated products.”

PSMA-targeting radioisotopes have reached a crucial tipping point, says Bander.  “When we characterized PSMA – its specificity for prostate cancer, the fact that 95 percent of prostate cancers were PSMA-positive, that cancer internalizes the PSMA-targeting antibody, that it’s upregulated by hormonal therapy, and that it’s a potential target in other types of tumors – interest started to build.  Then when we showed that if we administered a PSMA-targeting agent, we could actually validate in a patient that it was reaching the cancer, it increased even more.”

A big kick in the pants to the world of PSMA-targeting treatment came from striking results achieved overseas, discussed here.

Note: This is one of a series of stories I’ve just written on PSMA-targeting.  If you are seeing this as a solo story, click here for more.

 

In addition to the book, I have written much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

 

 

 

 

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Killing Metastatic Prostate Cancer with PSMA-Targeting Radionuclides

There’s some bright hope on the horizon for men with metastatic prostate cancer:  it’s PSMA-targeting therapy. This is different from PSMA-targeted imaging, which shows where small bits of prostate cancer are hiding in the body.  But it uses the very same building blocks.  Think of molecular LEGOS:  Instead of attaching the tracer molecule that can “see” prostate cancer, a different isotope (chemical brick), called a radionuclide, can be attached: one that can kill cancer.

PSMA stands for prostate-specific membrane antigen (PSMA), a protein that sits on the surface of 95 percent of prostate cancer cells.  Briefly, to recap the PSMA story so far, we have talked about how PSMA-targeting came to be, covered the first PSMA-imaging agent to get limited FDA approval, and the second imaging agent, which will be used more widely.  Now it’s time to talk about radionuclides.

“With the same chemical scaffold serving as both a diagnostic and therapeutic agent, the field of ‘theranostics’ has recently gained traction,” Martin G. Pomper, M.D, Ph.D., Director of Nuclear Medicine and Molecular Imaging at Johns Hopkins, told me in a recent interview.  Pomper’s team developed the small molecule PSMA tracer that is now the FDA-approved agent, PYLARIFY.  “Recent advances have really lit this form of treatment on fire.”

In Europe and Australia, and in international clinical trials, PSMA-targeting radionuclides such as 177Lu-PSMA-617 (called lutetium-177-PSMA-617, or LuPSMA), are being used to kill metastatic prostate cancer.  “In Australia, 177Lu-PSMA-617  proved superior to cabazitaxel in terms of PSA response and lack of significant adverse effects when compared head-to-head in the TheraP trial,” says Pomper.  “We are working with Novartis on a similar agent, called 177Lu-PSMA-R2, which has even fewer side effects, including lack of uptake in salivary and lachrymal glands.  We are hoping that agents using this molecular scaffold will be able to be outfitted with a variety of even more potent radionuclides than 177Lu.  It is anticipated that 177Lu-PSMA-617 will be FDA-approved at the end of this calendar year.”

In the international Phase 3 VISION trial, reported in June 2021, 831 men with PSMA-positive cancer (cancer that shows up on PSMA-PET) were randomly assigned either to receive LuPSMA plus standard of care, or standard of care alone.  Men who received LuPSMA were about 40 percent less likely to die and 60 percent less likely to have disease progression on scans, compared to the men who received standard of care alone.  After 21 months, cancer progression was delayed for longer: 8.7 months vs. 3.4 months among controls, and men in the LuPSMA group had better median overall survival: 15.3 months compared to 11.3 months in the control group.  Side effects of LuPSMA included fatigue, bone marrow suppression, dry mouth, and nausea/vomiting.

Note:  The TheraP trial compared LuPSMA to chemotherapy (cabazitaxel), but the VISION study did not include chemotherapy, immunotherapy, or other therapies that oncologists would otherwise try.  Oncologists will tell you that  any one therapy may not ever become the magic weapon for beating metastatic prostate cancer – but along with other weapons, PSMA-targeting radionuclides will be part of a pretty impressive arsenal.  Also, as LuPSMA and similar agents get FDA approval, you can bet that doctors will start giving them to patients at earlier stages, when cancer is more vulnerable and easier to kill, and that’s going to boost survival, too.

You might also be wondering about the cancer cells that don’t make PSMA.  New methods of treating them are on the horizon, too.  Pomper is developing new molecules and therapies to target “PSMA-invisible” forms of prostate cancer.  “We are working on agents that work through different mechanisms and can complement the PSMA-targeted agents,” he says.  “I believe that combining theranostics with immunotherapy, PARP inhibitors and other emerging agents – in addition to further optimization of dosage, dose rate and type of isotope of the PSMA-targeting agents – will be able to stave off progression of the disease for years, and that these patients will eventually succumb to ailments other than their prostate cancer.”  In other words, that one day, maybe not too far away, these new forms of therapy will allow men to die with, and not of, prostate cancer.

There are even wider implications, too:  “It took a long time, but now we’re seeing many exciting offshoots of our work in other forms of cancer, as well.  Some pretty amazing things are happening.”

We’re not done here.  I’ve got a lot more on PSMA-targeting therapy.  I want to put it in context, and also break it up into reasonably-sized chunks.  So bear with me: I’m doing this as a series, but to get it to you ASAP, I will post it all at once. Note:  If you are seeing this as a solo story, click here for more.

 

In addition to the book, I have written much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

 

 

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Block SRCs, Kill Prostate Cancer?

This is part of On the Horizon:  a series written with the sole purpose of sharing hope:  showing you some of the new treatments that are being developed to fight cancer that has defied everything else.  Because I write for the Prostate Cancer Foundation’s website, I get to interview scientists developing highly promising treatments that aren’t widely available yet, but they’re in the works.  Salma Kaochar, of Baylor College of Medicine, is one of these scientists.

How do you stop a runaway train?  Take a few seconds and think about it; feel free to draw from any runaway-themed movies you might have seen.

Well, you could go after the track: rip it up: a train can’t go very far without a track.  Get rid of its fuel:  this was an idea in “Air Force One,” where Harrison Ford dumped jet fuel in mid-air.  Slow it down:  in “Unstoppable,” Denzel Washington and Chris Pine tried to halt a runaway by pulling it from behind with another engine. This didn’t work for very long; next, they tried to engage the brakes – first on the individual cars, and then on the main engine.  Blow it up: If you didn’t really care about innocent bystanders or collateral damage, you could just take a rocket-powered grenade or heat-seeking missile and try to destroy the runaway engine… if you happened to have such a weapon, if you knew how to use it – and if, of course, this weapon actually works like you hope it will.

Metastatic prostate cancer is like a runaway train. Every day, scientists are getting closer to stopping it, with a drug or treatment that targets one of cancer’s weak spots.  Cut off its fuel:  That’s the reason for ADT (androgen deprivation therapy), shutting down testosterone and other androgens (male hormones) that drive the cancer; and also for androgen receptor-blockers, drugs like abiraterone and enzalutamide.  Hinder its ability to grow:  that’s the purpose of chemotherapy, and of drugs that target angiogenesis – like the tracks for the train, there are pathways cancer needs before it can get rolling.  But these types of drugs often don’t work for long.

Wouldn’t it be nice to target several of these ideas at once?  Not an either-or situation, but a “this mechanism and this one, too, and also this one.” 

That has been the dream.  What could be even better?  A drug that would not mess with the male hormones; something that would enable men to keep their testosterone and prevent the side effects of ADT.

We may have found one.  It’s preliminary, and probably two years away from clinical trials, but Salma Kaochar, Ph.D., Nicholas Mitsiades, M.D., Ph.D., and colleagues at Baylor College of Medicine seem to have found a promising new strategy that rips up the track, and dumps the jet fuel, and turns on the brakes – and causes, at least in mice, no collateral damage. 

It shortstops prostate cancer at the protein level and at the same time, turns up the immune system – in a way unlike any form of immunotherapy currently available– and doesn’t affect testosterone at all.

“We are developing a first-in-field approach to target the previously undruggable family of cancer-promoting genes for the treatment of both androgen receptor-dependent and androgen receptor-independent castrate-resistant prostate cancer (CRPC),” says Kaochar.  She presented her findings at the 2018 Scientific Retreat of the Prostate Cancer Foundation.

What is this secret weapon, and how does it work?  If we continue with our movie analogies – and pardon me for doing so, but otherwise this stuff is hard to explain – then it’s like that scene in “Raiders of the Lost Ark,” where Indiana Jones, faced with a fearsome, sword-wielding assailant, pulls out a pistol and shoots him.  He doesn’t try to out-fence a master swordsman.   He changes the game.

Kaochar and colleagues have found a potential game-changer, a target that no one has ever tried in cancer before: p160 SRCs, or “steroid receptor coactivators.”  These are “master regulators of transcription factor (key proteins) activity necessary for cancer cell proliferation, survival, metabolism, cell motility, invasion and metastasis,” she explains.  “In prostate cancer, they are required for the function of the androgen receptor and its variants.”

Transcription factors are proteins that act as a key to turn on a gene – just like a key in the ignition of a car.  Except here, if you have more keys, you can make the engine go faster.   “In CRPC, there is frequent overactivation of p160 SRCs,” Kaochar continues. “This results in increased androgen receptor activity, faster growth of the prostate cancer cell (more powerful and determined cancer cells), resistance to therapy, and bad outcomes.  Increased levels of these SRCs are associated with very poor prognosis.  SRCs are also important for the energy homeostasis (energy balance) in prostate cancer.”

The most deadly prostate cancers are addicted to SRCs.  They’re like crack for cancer. 

But guess what?  “SRCs can be reprogrammed.  They can be suppressed.”  And this can happen in localized tumors as well as in metastatic cancer.  Theoretically, there is no point in cancer at which this couldn’t start to work.  “Our goal is to find something to hit cancer at that late stage, where there’s absolutely no other treatment, where it’s all over, everywhere.”

In mice, Kaochar and colleagues are using “pulses” of treatment, not one continuous treatment.  Each pulse shuts down all the machinery cancer needs to grow, and also energizes the body’s immune system to fight the cancer.

Overactivation of SRCs appears to be extremely common in prostate cancer, and in other forms of cancer, as well.  So far, in laboratory tests using various types of aggressive, hormone- and chemotherapy-resistant prostate cancer cells (because men with prostate cancer don’t all have the same genetic mutations), 100 percent of prostate cancer cell lines tested in a dish have tested positive (see below) as being driven by SRC.

“These p160 SRC molecules are important in many cancers,” Kaochar says, “including uveal melanoma,” a particularly nasty form of melanoma that attacks the eye. “Uveal melanoma is a hormone-independent cancer, and it is heavily addicted to these molecules.”  Not only is uveal melanoma deadly; it is an “orphan disease,” rare, and lacking big financial support for research.  Kaochar’s research, funded by the Prostate Cancer Foundation, may lead to the first effective treatment for this disease, too.

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Could Controlling Metastatic Cancer Really Be Just a Matter of Tweaking?

If you’re a certain age – old enough to remember life before digital TVs – you probably know a lot about the fine art of tweaking.  If your picture was fuzzy, there were lots of ways to fiddle with the TV to try to fine-tune it.  There was the antenna, of course; actually, there were two, one up on the roof, and the rabbit ears on the TV set itself.  Then there were the knobs:  color, contrast, brightness, horizontal and vertical control.  It took a lot of trial and error, but tweaking was the key to a better picture.

Could controlling cancer be anywhere near that simple?  Well, in practice, it’s a heck of a lot more difficult, but the idea may be that simple:  tweaking the cancer cells, and also fine-tuning the normal cells.

Salma Kaochar and colleagues at Baylor are really developing several things at once: One is a sophisticated test to see if a man’s prostate cancer – and, quite possibly, anyone’s melanoma, breast cancer, pancreatic cancer, glioblastoma, ovarian cancer, etc. – is controlled by SRCs, which do various biological things, ranging from housekeeping chores like DNA repair, to controlling the metabolism, to controlling various proteins and driving cancer cell growth.  She is working on a simple test that works like a stoplight:  green means positive, yellow means maybe, and red means no. But the thing is, cancer might test red today, but as it continues to mutate and become more dangerous, it might test green in a few months. 

So far, 100 percent of the various prostate cancer and other cancer cell lines Kaochar has tested – in RNA sequencing and tests of more than 1,000 different genes – have come back green.  “More than 92 percent of the genome is coded by SRCs,” says Kaochar. “In prostate cancer and breast cancer, we have seen the same thing, and we believe it’s true in multiple different cancers.”

In cancer cells in a dish, “SRC 160 looks like a real vulnerability,” says Kaochar.  Jonathan Simons, M.D., medical oncologist and molecular biologist, and CEO of the Prostate Cancer Foundation, which has funded this work, describes it as “hitting the carotid artery.  If it works, it would be a stopper.”

But, “the more we learn, the more complicated the story gets,” Kaochar cautions.  “It’s exciting to have something that does so many things and has so much promise.  But at the same time, we have to carefully examine everything, and make sure there is no toxic effect.  That’s the spectrum where we’re really focused right now.”

Because this is first-in-field – a whole new class of drug – it will require a lot more testing before it can be tried in humans. Starting with cell cultures, then mice, then rats, then larger mammals.  “We just don’t know what their off-tumor effect,” on normal cells that are just minding their own business, “would be.”

Kaochar’s idea is that this drug would tweak the body: turn down SRC function in cancer – slowing down cancer cell growth, and also shutting down the cancer’s drive to metastasize – but also turn up the immune system at the same time, so the body can fight off the cancer.

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

 

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