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COVID-19 and Male Hormones: What’s the Connection?

Why has the COVID-19 virus killed many more men than women?  What does the virus have to do with male hormones?  Well, quite a lot, it turns out, and a lot of what scientists now know about this male hormone (androgen)-virus interaction comes from scientists studying prostate cancer.  Scientists whose research happens to have been funded by the Prostate Cancer Foundation (PCF).

Suddenly, the genetics of prostate cancer have also become the key to finding new treatments for this terrible coronavirus.  I write for the PCF’s website, so I’ve been lucky enough to learn about some of this research from the scientists first-hand.

It all has to do with genes and proteins:  That’s how the virus sneaks into the nose, throat and lungs, and does its evil work; how it enters the cells in the airway and starts reproducing like crazy, causing the cells to burst open.  The explosion of respiratory cells causes terrible inflammation, swelling, and congestion.  Worse, oxygen can’t get into the bloodstream.  This devastation can result in a ventilator in the ICU, or in death.

Think of this nasty virus as a con man who looks normal – like Fred MacMurray as Steve Douglas, the beloved dad in “My Three Sons.”  He seems benign, and he walks right into your house through your front door.  But oh, no! It’s actually Fred MacMurray as Walter Neff, the murderous insurance salesman in the iconic film noir, Double Indemnity!  By the time you realize he’s a bad guy, it’s too late! You’re in trouble.

COVID-19 does the same thing.  It attaches itself to a certain receptor called ACE2, which then tells cells, “This guy’s legit.  Let him in.”  ACE2 is the doorknob; that’s how the virus enters cells in the nose, airway and lung.

What does this have to do with prostate cancer?  The specific gene that makes it possible for the virus to grab onto ACE2 and keep entering and killing respiratory cells is called TMPRSS2.  PCF-funded scientists have studied this gene extensively in prostate cancer since 1988.  They know, from 32 years of research, what controls the TMPRSS2 gene that unlocks the receptor that lets in the virus:  androgens (male hormones).  TMPRSS2 is an androgen receptor-controlled gene.  

            Scientists believe they can stop the virus’s attack on the body by targeting TMPRSS2.

“In about half of all prostate cancer patients, TMPRSS2 is involved in a genetic event that can drive prostate cancer,” PCF-funded investigator Matthew Rettig, M.D., told me in a recent interview.  Rettig is a medical oncologist at UCLA and Chief of Hematology and Oncology at the VA Greater Los Angeles Healthcare System.  “The gene is tightly regulated by male hormones in prostate cancer.”  Male hormones, primarily testosterone, activate the androgen receptor and cause more TMRPRSS2 to be available on the surface of cells for the virus to enter.  “The question is, does TMPRSS2 in lung tissue behave in the same fashion as it does in prostate tissue?  We have good, correlative evidence that it does.

One way to do it is to shut down testosterone for a few weeks (being tested in TMPRSS2-targeted clinical trials discussed here, midway down the article).  “It turns out that if you suppress male hormones, that will suppress the production of the receptor,” Rettig says.  Basically, explains medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the PCF, “if you suppress male hormones, you reduce the total number of door handles the SARS virus can use to enter.”  Imagine evil, Double Indemnity Fred MacMurray, trying to get into the car where he commits the murder; there were no power door locks, so as he gets to each door, you push the lock down:  one, two, three, four!  You locked him out!

“Conversely,” says Rettig, “if you add male hormones to lung tissue, it will increase the expression of the receptor.  There is a lot of molecular/biochemical/scientific evidence that supports this concept: that the receptor for the virus is regulated in at least a similar manner in lung tissue as it is in prostate cancer tissue.”

Rettig continues:  “It is not a stretch for someone doing prostate cancer research to immediately see this connection and say, ‘Why don’t we temporarily suppress male hormones,” with available, FDA-approved drugs, “in male patients who are suffering from COVID-19, to see if we can immediately ameliorate the severity of the illness?’”

Don’t women have at least a small amount of testosterone?  “Yes,” notes Simons, “but while thousands of women have been infected, men are still more likely to become infected and die from COVID-19.”  Rettig adds:  “A striking study just reported that a huge proportion of women test positive who have no symptoms.  We think they actually may be protected by a combination of low androgens and high estrogen.  Work done by some of our colleagues at Columbia suggests that female hormones – estrogen and estrodiol – actually suppress the expression of the receptor.”  Then why not give estrogen to men?  “It does seem to suppress the receptor, but when it’s first given, in the first few hours,” there’s a temporary backlash, “a transient rise in the expression of the receptor that could make the disease more severe.”

This begs another question, and the answer has changed since I first interviewed Rettig a few weeks ago.  I asked him:  If shutting down the male hormones can stop the virus from invading the lungs, are men who are on androgen deprivation therapy (ADT) for prostate cancer protected?  He said, “Nobody knows yet.”  And that was true.  But since that time, another PCF-funded study of men with prostate cancer in Italy found that men who were on ADT were four times less likely to be infected with the coronavirus than men who were not on ADT, and five times less likely to die.  You can read about that here. And another approach, also being tested in clinical trials, involves a drug used in Japan to treat pancreatitis.  It is also a TMPRSS2-blocker.

It is amazing that in a matter of weeks, scientists have learned so much about this virus, including good potential avenues for treating it.

 

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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Whack-a-Mole and Prostate Cancer

Oligometastasis:  Good News from the ORIOLE Study

To the growing and hopeful list of strategies for attacking prostate cancer, let us add this approach:  Whack-a-Mole.

That’s how Johns Hopkins radiation oncologist Phuoc Tran, M.D., Ph.D., describes it to his patients.  The actual scientific name for this highly sophisticated strategy is stereotactic ablative radiotherapy (SABR, highly focused, intense doses of radiation), for men with oligometastasis – up to three small bits of cancer that have broken away from the main prostate tumor and started to grow elsewhere.

Previously, I wrote on Vital Jake and also on the Prostate Cancer Foundation’s website, about the Baltimore ORIOLE study, led by Tran, who also contributed greatly to our book.  Tran was enrolling patients in a small study to see if men with oligometastasis would benefit from SABR in addition to treatment of their primary tumor.

His strategy was a new one – part of a general rethinking of what represents curable prostate cancer.  The boundary used to be very clear:  prostate cancer was either confined to the prostate or prostate bed, or it wasn’t.   Like a light switch with no dimmer, there was no in-between:  a man with only one metastasis was believed to face the same fate, eventually, as a man with widespread metastases.  It was just a matter of time.

But Tran believed that the lines of prostate cancer were not so clear-cut as scientists had assumed; that instead of two circles – localized and metastatic cancer – that didn’t connect, we might be dealing with a Venn diagram, with oligometastasis as the critical area where the two circles overlap.  “It may be that the window of curability is wider than we thought,” he said last year, and we all hoped that he was right.

Tran and colleagues at Johns Hopkins, Stanford, and Thomas Jefferson University recently published results of the ORIOLE Phase 2 clinical trial in JAMA Oncology.  The results are promising:  54 men with oligometastasis were randomly assigned either to treatment with SABR or to observation.  To detect and keep track of the oligometastases, the study used PSMA-PET scanning, which uses a small molecule linked to PSMA (prostate-specific membrane antigen, found on the surface of prostate cancer cells) as a radioactive tracer.  This PSMA-targeting tracer can highlight areas of cancer as small as a BB – much smaller than can be seen on regular PET or CT imaging.  “PSMA-PET allows us to treat lesions we otherwise couldn’t see,” Tran explains.  “A CT or bone scan would miss those lesions, and patients would presumably not do as well.”

At six months, 61 percent of the men in the observation group progressed – compared to only 19 percent of the men who received SABR.  “We also saw a significantly decreased risk of new metastatic lesions using PSMA PET-CT” says Tran.  “The men in the SABR group did considerably better.  This is a definite signal that we can perhaps modify metastatic disease.”

This was a Phase 2 study, and “we need larger Phase 3 trials,” he says.  “But this is very positive, and we hope that in the future, we will be able to change the course of metastatic disease in some men.” 

Some interesting points here:  First, Tran and colleagues hope that “complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT).”  The key question, Tran says, is, “can we alter the natural history of metastatic prostate cancer with metastasis-directed therapy (MDT)?”  They don’t know the answer yet.  Most men with oligometastatic disease who get these spots of cancer zapped don’t experience a complete drop in PSA.  This, Tran says, suggests that “residual micrometastases are present but undetectable.” Does SABR simply reset the clock – does it keep pushing the snooze button?  Or, as the scientists hope, does it make the cancer less likely to form new metastases?

Bad Pioneers on a Bad Journey:  Tran and other scientists theorize that the spread of cancer is a story of colonization.  A few pioneers set forth on a journey to a new land.  At first, it’s touch-and-go; their survival is tenuous.  Just think of the early colonists in the U.S., from England, France, or Spain.  Until they took root in the new land, these nascent colonies were frail:  they needed reinforcements from their mother countries – medicine, weapons, tools, food – and “eventually they did survive.”  So it may be with the seeds of cancer; either the cancer cells themselves, or their messages (in the form of genetic and chemical telegrams) are dispatched to the primary tumor, the mother country.  If the mother country is no more – if it has been eradicated by surgery or radiation – then small cancer outposts might get similar support from visiting each other.  But if those outposts are destroyed by SABR, even if there are a few cancer cells remaining in the tissue or bloodstream, it doesn’t matter:  the environment is too hostile, and the numbers are too few for new colonies to survive – “or, if they did, it would take much longer.”

“It’s like Whack-a-Mole”:  In the ORIOLE trial, Tran and colleagues looked for circulating tumor DNA (ctDNA), and identified certain gene signatures that can tell if a man is more likely to respond to SABR.  “Patients who don’t have these mutations responded very well,” he says.  They also have learned from this and other research that men with oligometastasis fall into three basic groups.  “Some men do really well after one course of SABR,” with no recurrence of cancer.  A second group of men have a small recurrence.  “Another site pops up; a microscopic metastasis that we couldn’t see before establishes itself into a macroscopic metastasis.  It’s a limited return of cancer and it responds to another round of SABR.”  Then some men, after a few months, have multiple new areas of cancer.  “For these men, the SABR doesn’t control the disease at all.”

Imagine a green lawn, with one or two dandelions, Tran tells his patients:  “You can pluck those two or three weeds, and wait and see.  Sometimes you get lucky; sometimes another weed or two pops up, and you pluck them.  It’s like Whack-a-Mole.  You can do that for a while,” with repeated SABR treatments.  As the scientists reported:  “If a single round of MDT arrests the progression of some, but not all, lesions, subsequent rounds of MDT might salvage the remaining disease, until what remains is inadequate to support a metastatic phenotype.” Basically, for some men, a treatment strategy might be to keep knocking the cancer down until, like a prizefighter who’s taken one too many blows to the head, it can’t get back up.  Imagine:  punch-drunk prostate cancer that may still be staggering around, but can’t raise a fist.  Wouldn’t that be nice!

That probably won’t work in every man, Tran says.  “Unfortunately, sometimes there will be a whole bunch of seeds all at once, and at that point, you need weed killer all over the lawn,” or systemic therapy.  However, SABR plus ADT, androgen-blocking drugs, or chemo might one day provide “the multipronged attack required to cure this disease.”

Looking ahead:  In a follow-up trial, called RAVENS, men with oligomestatic prostate cancer are randomly given either SABR alone, or SABR plus radium-223 (Xofigo).  “What we have seen in the men in that second group – the ones who have more isolated spots of cancer popping up – is, they’re not recurring where they received the SABR, but in areas that were microscopic, and commonly in the bone.”  Radium-223 targets cancer in bone.  “It releases a radioactive particle that is very toxic but is so focused that it only kills in a radius of two-three cell depths.  It’s ideal for microscopic disease.”

More and larger studies are needed, but in the future, Tran envisions, men with oligometastasis will require more vigilant monitoring, and ideally, regular follow-up PSMA-PET scanning.  “This has the potential to be practice-changing.  We are very excited by our results, and by the potential to modulate the course of metastatic prostate 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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