The Story of Gerry Potter, The Discoverer of Zytiga

BY MARK SCHOLZ, MD

Zytiga has rapidly become the treatment of choice for prostate cancer resistant to standard hormone treatment with Lupron. It is effective and well-tolerated. Given the immense success of this product, I find the story of its discovery 22 years ago quite interesting. What follows is a heavily truncated version of Jerry’s story published on the web in 2010. You can read the full story by googling “Gerry Potter” and clicking on the 4^th or 5^th entry.  

In 1990, Dr. Gerry Potter, having just finished his PhD, was in his first week of work at the Institute of Cancer Research in London's Royal Cancer Hospital. His colleagues on the drug discovery program, Prof. Mike Jarman and Dr. Elaine Barrie, wanted to target a male hormone-producing enzyme called CYP17 because prostate cancer feeds on testosterone.

A laser-guided bullet to target CYP17 was needed. Block this enzyme and you took away the cancer's exclusive food supply. "The idea was to starve the tumor to death, not attack it directly," explains Gerry.

They asked their new scientist to design a drug that “jammed”  the lock of CYP17. Easier said than done. To build a jamming key you needed to know what the lock looked like. No one did. You couldn't see it under a microscope. "You have to work it out from the inside," he says. "It's a bit like a glove. To know its shape, you need to understand the hand that fits it. You have a palm and fingers and thumbs. You have to work out how they all fit together."

Gerry worked on hunches and hypotheses, using his knowledge of the enzyme's basic components to scribble down different possible structures. Then he saw it, or rather he imagined it. "It was a Eureka moment," he says. "You instinctively know when something is right."

Now that he had the lock, he had to build the key to block it. That took a fortnight – a heartbeat in the time scale of hard science. "I developed a new chemical reaction to synthesize it," he says matter-of-factly. "What I was trying was really difficult and couldn't have worked predictably at any stage. Yet everything fitted into place. It worked first time."

Then came the boring part: the making of "analogues" –  a hundred near replicas of abiraterone, so no-one could make a copycat variant and claim the idea as their own. "None worked as well as the first," says Gerry, still slightly awed by that fact. "Everything came so easy."

Everyone involved felt the hand of history on their shoulders as abiraterone astonished participants in laboratory tests. The best prostate cancer drug on the market in 1990 – ketoconazole – had a cancer inhibiting activity of 10. "You need that number to be as low as possible," says Gerry. Abiraterone scored 0.001 – making it 10,000 times more potent than ketoconazole.

"It was, indeed, a magic bullet," says the scientist.

He "scaled up" the drug, so it could be produced in kilogram quantities – a requirement for the patent. The patent was eventually filed in 1994 through a venture capitalist company called BTG that had funded much of the supplementary research. BTG then sold on the team's hard work to Boehringer Ingelheim, a German pharmaceuticals giant with the financial muscle to support the fledgling drug through the inevitable years of clinical trials.

The people at Boehringer, however, became concerned when trials of abiraterone suggested it caused the depletion of cortisol, a hormone vital to health. The company cashed in its chips with abiraterone, selling the drug for $40 million to Cougar Biotechnology. Ultimately, pharmaceutical giant Johnson & Johnson (Janssen Biotech) bought Cougar Biotechnology for $1billion.  

Zytiga’s impact on lowering cortisol was easily solved by administering it with prednisone, a commercial form of cortisol.  Since Zytiga has so few side effects we have found safe ways to combine it with other effective therapies like Taxotere or Provenge.

Gerry and his team overwhelmingly succeeded in improving the lives of thousands of men with prostate cancer.

Confessions of an Anxious Man

BY RALPH BLUM

Like every man I know who is living with prostate cancer, I’ve had my bad moments. But right at the start, during the phase known as “newly-diagnosed,” I knew the odds were in my favor; knew I could die with it not from it. Now, after more than two decades of successfully and peacefully co-existing with this disease, I am once again feeling anxious and at risk.

I have succeeded in one area: the treatment I have undergone has been minimally invasive: no surgery, zero radiation, no chemo. Only a stint of hormone blockade, aka androgen deprivation therapy, and/or Testosterone Inactivating Pharmaceuticals (TIP). And even then, instead of the conventional triple medication—Proscar, Casodex and Lupron—being a minimalist rather than a fan of saturation bombing, I took only Lupron. Still, since there is no question about prostate cancer being testosterone driven, it was appropriate to choose TIP as the least invasive treatment option and, in my case, reduce my testosterone level to that of a pre-pubescent boy.

           

What else did I do to “fight” the cancer? I confess that my behavior as a prostate cancer patient does not receive high marks:  slovenly attention to weight (I’m 5’9” and weigh 218). Diet? Despite my wife Jeanne’s best efforts, I was only part time successful. Exercise? A stationary bike at my neighborhood YMCA, 20 minutes twice a week; no weights work. I am not proud of my record.

Prostate cancer specialists are now rethinking the validity of PSA monitoring. Still, as it was general practice with the option known as “Watchful Waiting,” I was regular in getting my PSA recorded. And until about six weeks ago, my levels were reasonable for a 79-year-old semi-careful patient of a conscientious, competent oncologist, my writing partner, Mark Scholz.

Then, in what might be called “overnight” after two decades of stability, my PSA doubled, vaulted up to 23 and change. And I confess, my sleep is being riven with anxious thoughts. The all but forgotten  “What  if . . .” assault has begin again earnest, with its companion stomach acidity, staring into the darkness, a renewed sense of urgency and, most upsetting, the writing on the wall has become the mirror image of my mantra: Die with it not from it.

However, since my last PSA test, I did undergo a form of heavy duty stress: two surgical procedures for kidney stones. And since surgery—together with heavy lifting, bike riding and recent sexual activity—is known to drive PSA to unrealistic levels, following any of these stressors, you are advised not to be re-tested for a good month or more.

Furthermore, although I was unaware of it for several months, I have been host to a nasty infection known as Proteus Mirabilis (More about that rabid puppy later!). Remembering a previous scare when my PSA suddenly jumped to an alarming level due to infection, I need to undergo a course of antibiotics—in my case Cipro—and then get another PSA test, and a rectal probe with analysis of prostatic fluid to determine whether the infection was actually the cause of my elevated PSA.

Then I will want two essential consults.

First, I need to see Duke Bahn, MD, radiation oncologist, and for my money, the world grand master of the Transrectal Color Doppler Ultrasound for Diagnosis, monitoring with Active Surveillance, and the management of Recurrent Disease.

           

And finally, I will consult with Lisa Chaiken, MD, radiation oncologist at St. John’s Medical Center in Santa Monica, and herself a grand master in the forefront technique of Intensity Modulated Radiation Therapy (IMRT), the only radiation procedure I would feel even provisionally comfortable undergoing.

So first things first: I just came back from my neighborhood CVS Pharmacy with 39 tablets of 500mg Ciprofloxacin HCL. Took the first tab in the parking lot. I’ll complete the two-a-day course of antibiotics; then redo the PSA and get the opinions of the prostate mavens I trust. But whatever the case, I have decided that it is time for definitive treatment—aka cure. Living with low testosterone is downright debilitating.

Enough is enough.

Deadly Bedside Manner

BY MARK SCHOLZ, MD

Physicians are routinely trusted with privileged information, information so intimate that even a spouse may not be privy to it. Patients naturally expect their doctors to handle such information wisely and professionally. We expect a certain degree of thoughtful kindness and respect from doctors since they have unbridled access to the inner sanctum of their patients’ lives.

However, successful doctors who are caught up in the swirl of complicated and busy schedules constantly facing a stream of frightened and anxious patients, sometimes become desensitized leading to a brusque and calloused demeanor.  For these doctors, illness has become the norm, hardly something to get excited about.

A study published in this week’s New England Journal of Medicine on the incidence of suicide and heart attacks after a diagnosis of cancer, strikes a cautionary note. Dr. Fang and colleagues from the Karolinska Institute in Stockholm, reported that soon after a diagnosis of cancer the incidence of suicide and heart attacks jumped 1,000%.

The study reported that the more serious the diagnosis, the greater the risk of patients being literally frightened to death. A diagnosis of lung cancer increased the risk 2400%. The risk was 3200% when esophageal, liver or pancreatic cancer was diagnosed. With prostate cancer the increased risk was “only” 600%.

I have always had a strong intuitive sense that mishandling a patient’s psychological world could be “unhealthy.” The thought that it might be potentially deadly is sobering. 

You wouldn’t think that doctors could be so insensitive that they would telephone patients on a Friday afternoon to inform them of their cancer diagnosis.  Believe me, it happens. 

Potentially bad news needs to be imparted in a supportive environment. Emotional support comes from the physical presence of family members or friends. Professional support comes from having a plausible plan of action for treating the cancer.  In my more than two decades of treating prostate cancer, I have learned that people’s frightened concerns about the future are almost always radically worse than the truth.

The new Swedish study shows how important it is to make sure that patients with recently diagnosed cancer don’t become isolated.  Cancer patients should never be asked to “go it alone.”

Homage to Tom Stamey, MD

BY RALPH BLUM

Looking back on my two-plus decades of coexisting with prostate cancer, I see my travels as an odyssey; or perhaps hegira comes closer to the mark, since it has indeed been “a flight to escape danger.” Either way, along the route, at meetings, consults, conferences, I have listened to the opinions and prejudices of eminent healers, men and women I would—all matters of disease aside—be pleased to count as friends.

Among them are a number of urologists and oncologists, all of whom had at least two things in common. First, at some point in their careers they had been either students or colleagues of Thomas Stamey, MD, a leading expert on prostate cancer and godfather and midwife to the PSA blood test. And second, a recognition of the modesty and humility with which Stamey regards his own achievement.

The literature of prostate cancer is hardly known for quotable remarks. Like a few lines you come away with after seeing a good play. But then the only “theatrical” aspect of prostate cancer is the OR. And while a compelling case can be made for too many urologists (aka surgeons) appearing far too frequently in those theaters, I have only one memorable quote.

It is something Dr. Stamey said, his terse prophecy that is pinned to the shelf above the desk where I work, and that has appeared on more than one occasion in my writing. It is this: “When the final chapter of this disease is written, it will prove that never in the history of oncology will so many men have been so over-treated for one disease.”

According to Stamey, prostate cancer is a disease all men get if we live long enough, so given an excuse to carry out a biopsy, doctors will likely find cancer.  “Our job now,” said Stamey, “is to stop removing every man’s prostate who has prostate cancer. We originally thought we were doing the right thing, but we are now figuring out how we went wrong. Some men need prostate treatment but certainly not all of them."

Stamey also reminds us that almost all men over 50 years of age start to develop benign prostatic hyperplasia, and that PSA is related today to the harmless enlargement of the prostate and not to cancer. Although the PSA test is still useful in monitoring patients after surgery, as an indicator of residual cancer, it is not a reliable predictor of the amount or severity of prostate cancer.  Stamey recommends a yearly digital rectal exam for all men over 50, and his group at Stanford is currently working on finding a blood marker that could indicate the more aggressive forms of cancer.

The most significant question is how to combat the fear factor. Many urologists will likely continue to perform biopsies based on PSA results, find early stage cancer, and recommend immediate—and as it turns out,  in most cases, unnecessary— treatment. So in what Stamey calls “this heavily screened country” it is up to each of us not to let fear dictate our decision making, not to yield to the emotional appeal of “cutting it out.”  If we decided to choose a Patron Saint of prostate cancer, you know who my candidate would be.

Consider that prior to the advent of PSA testing back in 1987, 1 of 41 men in the United States died of prostate cancer.  In 2009, with almost universal PSA screening and early treatment, the risk of dying from prostate cancer has improved, but not as much as you might think.  Presently the risk is 1 out of 53.

The cost of this progress is substantial: Prior to PSA testing 90,000 men were diagnosed with prostate cancer annually.  Now 200,000 men are told they have prostate cancer every year.  And, an additional 800,000 men undergo a prostate biopsy without being diagnosed with the disease.

So if your PSA is elevated, before you commit to irreversible and unpredictable bodily invasion, take a minute to consider the odds, and mull over Tom Stamey’s prophecy: “When the final chapter of this disease is written . . .”