Although the global pandemic-causing coronavirus called COVID-19 has only recently taken over all our lives – killing more Americans in just eight weeks than died in the entire Vietnam War – scientists already know quite a lot about it. For instance, they know how the virus sneaks into the nose, throat and lungs, and does its evil work. They know how the virus enters the cells in the airway and starts reproducing like crazy, causing the cells to burst open with billions more viruses. The explosion of respiratory cells causes terrible inflammation, blood clots, swelling, and congestion. Worse, oxygen can’t get into the bloodstream. This devastation can result in a ventilator in the ICU or – for more than 300,000 people worldwide so far – in death.
What is COVID-19 (known to scientists as SARS-CoV-2)? 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.
The virus 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 else do scientists know? Well, they just happen to know the specific gene that makes it possible for the virus to grab onto ACE2 and keep entering and killing respiratory cells: it’s called TMPRSS2. And wait! There’s more! Our scientists, in particular, here at the Prostate Cancer Foundation (PCF), know a whole lot about TMPRSS2 because they’ve studied it extensively in prostate cancer since 1998. They know, from 22 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. And they have a way to stop it.
“In about half of all prostate cancer patients, TMPRSS2 is involved in a genetic event that can drive prostate cancer,” says PCF-funded investigator Matthew Rettig, M.D., UCLA medical oncologist and Chief of Hematology and Oncology at the VA Greater Los Angeles Healthcare System. “The gene is tightly regulated by testosterone in prostate cancer.” Male hormones, primarily testosterone, activate the androgen receptor and cause more TMPRSS2 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. It turns out that if you suppress male hormones, that will suppress the production of the receptor.” Basically, explains medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of 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, you may increase the expression of the receptor. There is a lot of molecular/biochemical/scientific evidence from multiple PCF-funded laboratories 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.”
The PCF/VA study team, individually and collectively, had an “Aha!” moment. Rettig explains: “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.”
And so, in rapid response over the span of only two weeks, the Veterans Health Administration and Federal government accomplished something unprecedented: they did the clinical trial-approving equivalent of the Cannonball Run, the unsanctioned speed record from Manhattan to California (broken again in April during the COVID-19 shutdown, when a team made the drive in 26 hours and 38 minutes). In the world of clinical trials, in effect, they hauled ass. They zoomed into action, and the VA is now ready to enroll Veterans in the HITCH trial.
HITCH stands for “Hormonal Intervention for the Treatment in Veterans with COVID-19 Requiring Hospitalization,” and this Phase 2 randomized, controlled trial will be carried out at four VA medical centers in COVID-19 “hot spots” around the country: In Los Angeles and Seattle, and at two VA hospitals in New York, Manhattan and Brooklyn.
Who’s eligible? Male Veterans over 18 “who are sick enough with COVID-19 that they are in the hospital,” not outpatients who have tested positive for the virus and don’t feel sick enough to be hospitalized. “Most outpatients are going to do well on their own,” says Rettig. At the other end of the spectrum are men who are “severely, critically ill, in the ICU, on a ventilator.” Those patients, he believes, at that point may actually be suffering more from the immune system’s all-out war on the virus, than on the virus itself. “We’re trying to get that ‘sweet spot’ in the middle: to slow down the replication of the virus in men who are sick enough to require treatment, but not sick enough to be in the ICU.”
There’s no other age restriction. “Clearly, there’s evidence that young, healthy men can contract this virus despite being healthier and having a more robust immune system. We think that may be related to the fact that they have more male hormones and androgen receptors.” Also, in China, Italy, Spain, South Korea, the U.S., and other countries, men have been two to three times more likely to die from the virus than women. The male hormone connection “also may account for the relatively benign course of the infection in children.”
Again, what about women? “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 estradiol – 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. We decided to avoid using estrogen in men.”
One more question: 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? Early data from over 4,000 COVID-19-infected men in Italy suggest that this is possible. A PCF-funded study of men with prostate cancer in the Veneto region found that men with prostate cancer who were taking ADT with low testosterone on treatment were 4 times less likely to be infected with the coronavirus than men who were not on ADT, and 5 times less likely to die. Closer to home, Rettig has looked at the entire VA database, and found only 23 men with COVID-19 who are on ADT. “The numbers are just too low to make any statistical conclusions about whether or not men on hormone-suppressing therapy are protected from COVID-19.” But it certainly is an intriguing possibility, worthy of further study.
The HITCH trial will happen fairly quickly: Rettig estimates a 90-day enrollment period to study 198 patients, “with another 30 or so days for completion of the clinical effects in all patients.” The participants will be randomly assigned either to receive “best supportive care,” the standard care offered by the hospital, or best supportive care plus a shot of Degarelix, a drug that shuts off testosterone for about a month. Note: Men, do not fear this drug. It’s FDA-approved and being safely used by hundreds of thousands of men long-term, but its effects are temporary! “When it’s out of the patient’s system, the testosterone level will lag a bit, probably for a few weeks, but we expect that all patients will recover their regular testosterone level. This is just one dose that will last four weeks.”
How in the world did a clinical trial get fast-tracked in just two weeks? The VA Medical leadership, from the top down, was ready, because of the working partnership between the VA and PCF. The infrastructure was there. The hospitals in this trial are VA-PCF Centers of Excellence, and Rettig happens to be one of the co-leaders of this collaboration. “The VA and PCF have been working very closely together,” says Rettig. In this case, “not only was there an overlap between prostate cancer research and lung research, in terms of how male hormones may regulate the viral receptor. There was also an overlap in prostate cancer clinical research and COVID-19 cases and the density of cases,” (the “hot spots” just happen to be in cities where there are PCF-VA Centers of Excellence). “We knew all of the investigators at these sites, knew they had research coordinators, knew the clinical trial infrastructure was in place. In terms of getting the study up and running, that required influence by PCF, which supported the seminal work in demonstrating the relationship between the male hormones and the viral receptor.”
There was also a bit of serendipity: Rachel Ramoni, D.M.D., Sc.D., the Chief Research and Development Officer for the entire Department of Veterans Affairs, has bimonthly meetings with the PCF-VA physician-scientists as a part of the PCF-VA Precision Oncology 5-year partnership. She had set up a VA Rapid Clinical Care and Response COVID-19 steering committee, and during one of the regular VA-PCF cancer research partnership calls, Rettig mentioned his idea to her. It just so happens that two other researchers, “one at Columbia, and one at the University of Alabama at Birmingham, had independently come up with the same TMPRSS2 hypothesis from coronavirus research in March coming from Germany, and told Rachel about it. When she heard about it from me,” the third time proved to be the charm. “We presented this idea to the COVID-19 steering committee, rapidly put together the protocol, and the VA facilitated simultaneous regulatory documents – a huge undertaking. A regulatory review and a monitoring review were done concurrently. We’ve had incredible support from the VA, and this is a new record. Normally, something like this would take 10 to 12 months minimum to activate. Everyone dropped everything, realizing the importance of opening clinical trials for COVID-19 patients. This is urgent.” For more information, contact Samantha Tran, Study Coordinator at UCLA: 310-478-3711 x44917.