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November 3, 2022 · 2:00 pm

Support Movember!


Hi Everyone,

I’m on a bit of a sabbatical from writing for the blog. I will probably pick it up again in the spring and at least try to write something quarterly. Meanwhile I hope you will join me in supporting Movember your own way. I won’t have a personal site this year, but you can set up to make a contribution here if you wish: https://us.movember.com

Please consider starting your own campaign and invite your friends and family to support the cause. It’s not that hard!

Meanwhile I hope everyone has a safe and happy holiday season and I’ll see you next year.

Michael

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December 18, 2021 · 4:18 pm

Molecule of the year: PSMA


To view this on my blog, sign up for future posts, and search for other posts regarding prostate cancer issues, please click on this link.

We made it around the sun another time, and in spite of Covid 19, are still here to thank you for your interest in this blog and most especially for your support of prostate cancer research via my annual efforts to grow a moustache and help Movember raise funds for prostate cancer research. A heartfelt thankyou!!

With all of the “Ten best” and “top songs” lists that appear this time of the year, I thought I would expand a bit on PSMA as a real game-changer that is coming on strong to change our management of prostate cancer. So what is Prostate Specific Membrane Antigen?? Well, first of all, I think you know what an antigen is, or if not, here’s a timely clue: Spike protein. When you received your vaccination with Moderna, Pfizer or J&J vaccine, you were exposed for the first time to a foreign protein that the SARS CoV2 virus (COVID-19 disease causing) uses for entering the cells that line your airways. Your body responded to this antigen (foreign protein) by developing antibodies – the levels (titers) of which prevented you from getting COVID, or at least prevented you from getting very sick. Antibodies are very specific proteins made by the B-cells of your immune system that bind to foreign antigens and are the first line of defense against invaders.

Now, if you inject a mouse with human prostate cells, the mouse will recognize all sorts of the proteins as “foreign” and make antibodies against them. In such an experiment, Wright and colleagues in the early 1990’s found that one such antibody could be useful in detecting prostate cancer. It turned out that the antibody was detecting a protein expressed on prostate cells, but also tumor blood vessels and the salivary gland that became known as PSMA. Unlike PSA, this protein is bound to the membrane of the cancer cells and doesn’t circulate in the blood stream. PSMA is actually an enzyme involved in the normal absorption of folate (a vitamin) from the intestine, but for unclear reasons, it is dramatically over expressed by prostate cancer cells. Over the next 25 years, numerous researchers worked on tagging radioactive isotopes to antibodies that would bind to PSMA and therefore could be used to detect prostate cancer or if the radioisotope was powerful enough, kill prostate cancer cells. One of the challenges, however, in using radio labeled antibodies is their size, resulting in a lot of non-specific “sticking” in the liver, spleen and elsewhere. A better approach evolved by finding small molecules that would stick to the PSMA enzyme activity site as illustrated in this figure:

As a result of this research, it became possible to develop highly sensitive PET scans that can detect much smaller metastases of prostate cancer than any previous bone or CT scans were able to do. Gallium and Fluorine isotopes hooked to the peptide (617) are rapidly becoming available in PET scan centers across the United States (and have been available for the past 3-5 years in Europe, Australia and elsewhere) and will likely become approved as the new standard for staging newly diagnosed and PSA recurrent metastatic prostate cancer. Moreover, the isotope Lu177, that emits strong beta radiation (electrons) can be attached to peptide 617 and kill cells that express PSMA.

In the VISION trial, published this year in NEJM, the use of Lu177 PSMA to treat advanced prostate cancer patients who had progressive disease after previous treatment with a second generation hormone agent (such as Zytiga or Xtandi) plus chemotherapy with a taxane (Taxotere or Jevtana) were scanned with Gallium labeled PSMA then treated with Lu177 PSMA. The treated men were compared to alternative “standard of care” which might have included other forms of chemotherapy for example. The results were extraordinary as shown in these curves.

So for this year, I’m nominating PSMA as the molecule of the year. PSMA PET scans will likely be the only scans needed to follow prostate cancer metastases, and are already being used in newly diagnosed patients with high risk disease to make sure we don’t miss something. Further, if there are only a few metastases, we can treat these at the same time we treat the prostate with hopes that some of the patients with metastatic disease can still be cured. And ongoing research is underway to evaluate the use of Lu177 PSMA in earlier patients without resistant disease. Great progress and I leave you with fond wishes to you and your family for a healthy (VACCINATED) 2022!

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November 1, 2021 · 5:29 pm

Join me fighting prostate cancer in the “Hairiest month of the Year!”


It’s that time again. A scraggly moustache may be better than none at all, and this is the organization that has done the most, along with PCF, to make prostate cancer history. Start your own fund raiser here.

Or if you don’t want to fund raise on your own, feel free to join my campaign by visiting my Movember Website.

Movember has made a HUGE difference in prostate cancer awareness globally by sponsoring research at every level -from clinical to basic science and the creation of data bases like the GAP3 project. Many of the posts I have written this last year like the ones on PSMA PET scans and Lu177-PSMA therapy are the direct result of Movember funding. Let’s keep the progress rolling!

Thanks for your consideration,
Michael Glode

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October 26, 2021 · 12:36 pm

Here’s what you should “eat” to fight prostate cancer…


To view this on my blog site, sign up for future posts, and search for other topics I have covered on prostate cancer, please click here.

OK, I will admit right up front to bait and switch. In the last month I have seen two of my patients who are what the public health aficionados call “positive deviants“. One man is a professional who still goes to work every day. I have been seeing him for about 5 years; he has metastatic cancer in many bones and lymph nodes, a PSA in the 100’s, yet other than being a bit too thin, carries on with his life helping other people in his chosen profession. The second gentleman looks like an olympic athlete – great muscle preservation, a military posture, and also continues to work at his regular job in spite of having “mCRPC” which most readers will know as metastatic castrate resistant prostate cancer. What is it they do far more than most of my other patients? What is their secret diet? …EXERCISE

In this piece from the New York Times on heart health, Dr. Emery, a cardiologist, refers to exercise as a magic pill. “It’s just that you can’t swallow it, you have to earn it,” he notes. You need to click on that hyperlink and read the whole article. These are the benefits for heart health:

  • It enhances the cardiorespiratory system.
  • It increases HDL cholesterol.
  • It lowers triglycerides, a type of fat that circulates in the blood.     
  • It reduces blood pressure and heart rate.      
  • It lowers inflammation and improves blood sugar control.

Best of all, exercise is the type of medicine that appears to produce benefits no matter how small the dose.

But what about prostate cancer you might ask? The studies there are compelling. In a recent article from Taiwan, 125 patients who were treated with ADT and radiation for high risk prostate cancer were studied for changes in body composition. The patients experienced a 5.5% loss in skeletal muscle over 180 days, and each 1% loss of the skeletal muscle index resulted in a 9% increase in non-cancer mortality! Although it is a small study and it is shocking, but it illustrates the problem of taking testosterone away from older men. You don’t need to rely on small studies however. In the Health Professions Follow-Up Study, 2705 men diagnosed with prostate cancer were followed from 1990-2008. “Men with ≥ 3 hours per week of vigorous activity had a 61% lower risk of PCa death (HR, 0.39, 95% CI, 0.18 to 0.84; P = .03) compared with men with less than 1 hour per week of vigorous activity. Men exercising vigorously before and after diagnosis had the lowest risk.”

So, the message is clear. Compared to any “diet changes” you can make, or supplements you might take, exercise is definitely more important to enhance your chances of surviving prostate cancer. Ideally, you should work with a trainer who can help you develop an individualized program that takes into account your current physical fitness. From the NYT article, here is a place to start if you don’t have access to a trainer:

“Anything is better than nothing. But the ideal dose of exercise for adults, according to the Centers for Disease Control and Prevention, is as follows:  

  • 150 minutes of moderate-intensity aerobic exercise a week.      
  • 2 sessions of about 30 minutes each of resistance training a week.

You can spread the aerobic activity throughout the week however you like, such as 30 minutes five days a week, or 50 minutes three days a week. Examples include running, swimming, brisk walking, riding a bike, playing basketball or tennis, and doing yard work. As for strength-building activities, ideally, you should set aside at least two days a week for 30 minutes of exercise that works the major muscle groups, such as the legs, back, shoulders and arms. What counts as strength training? Lifting weights, using resistance bands, doing bodyweight exercises like yoga, push ups and sit ups, and even heavy gardening with a lot of digging and shoveling. Vigorous exercise should get your heart rate up to 70 to 85 percent of your maximum heart rate. Not sure what that is? Here’s how to calculate it.” I also recommend your resistance training should utilize weights that cause your muscle group to “fail” on the second or third set of repetitions.

So there you have it – how to change your “diet” to beat prostate cancer. Definitely not as easy as just avoiding red meat and increasing soy products, but almost certainly the most effective thing you can do. Movember is coming up. Time to MOVE!

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July 28, 2021 · 2:18 pm

Cancer Camp and Survivorship


A cancer diagnosis affects every patient in a different way. However, regardless of what type of cancer is involved, it is a cold water “slap in the face” that we all share the same fate: “our days are numbered” – something everyone knows but we generally find it more convenient to simply not think about.

Prostate cancer, in my opinion, is somewhat different in this regard for most men. First, like all cancers, it is clearly a disease of aging, but even more so. The median age at the time of diagnosis is 66 years. This means the majority of newly diagnosed men have lived a reasonably long (and hopefully healthy) life. There has been time to deal with other health threats, watch children grow, and usually face the deaths of parents or close family members. However, the good news is that the vast majority of men will still have the opportunity for enjoying many more years of living.

Taken from the US SEER database: https://seer.cancer.gov/statfacts/html/prost.html

In fact, regardless of race or ethnicity, over 90% of men newly diagnosed with prostate cancer will be alive in 10 years. These data hold true even for men with regional disease, but fall off rapidly if metastatic disease develops. And there is continued improvement in treatment for the metastatic patients as well. In a recent article looking at three large studies for the benefit of second generation androgen receptor antagonists (enzalutamide, apalutamide, darolutamide) to delay metastases and improve survival, even men >80 years of age clearly did better than before.

From Lancet Oncology, July 23, 2021 https://doi.org/10.1016/S1470-2045(21)00334-X

So the question becomes, “what will you do with the time you have left?” regardless of how long that is. My thought, having just returned from volunteering at the Epic Experience cancer camp, is that it always good to take some time and reflect on how you want to spend that time. Write another paper? Start another company? Make even more money? Grasp for the latest treatment option? Or potentially reconsider family and friends and what really matters to you. The Epic organization has had trouble recruiting men to their camps, but for the men who have come, their perspectives have been altered in very positive ways as you will see in this video. Many more women come to the camps, just as women have led the way in advocating for breast cancer research, and in general reaching out via support groups. We have a lot to learn from them!

There are many support groups out there for prostate cancer survivors of all stages. Prostate Cancer Foundation has put a nice list together here. And if you would like online support for specific issues, Movember’s True North initiative has great articles to help you here.

The bottom line for me, having had a chance to “get back to camp”, is that we can all use a little encouragement to get out there and live again as we come out of our COVID isolation. I hope you will do just that this summer!

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May 3, 2021 · 12:39 pm

Immune-oncology seminar tomorrow: May 4, 1:30pm EDT


Dear subscribers,

My normal goal is to send out a new post only once/month since, if you are anything like me, getting more and more emails is annoying to say the least. I am making an exception this month because I just received a reminder about a seminar I think many of you might enjoy. I have tried to do a few posts on this rapidly evolving treatment modality for you here, and here, and here.

For a more sophisticated education, designed for patients and taught by real experts, you may wish to register for the American Association for Cancer Research Seminar, “The Promise of Immuno-Oncology.” Here is the link:

The Promise of Immuno-Oncology
Happy learning from the AACR, one of my favorite societies!

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February 28, 2021 · 10:23 pm

Return to Estrogen?


To view this essay on my blog site, sign up for future posts and search for previous topics, please click here.

Remarkably, estrogen was discovered to be a cancer driver for breast cancer by surgeons in the late 1800’s but it was 5 decades before the relationship of hormones to prostate cancer was discovered. George Beatson had considered performing oophorectomy for women with breast cancer because the procedure was successful in prolonging lactation in cattle. His first patient experienced a complete remission from soft tissue breast ca metastases and lived another 4 years. He later said that he thought this treatment would induce “fatty degeneration” of malignant cells.

The relationship of testosterone as a driver of prostate cancer is credited to Huggins and Hodges, who found that either surgical castration or administration of estrogen to men with prostate cancer could reduce what was then the only known marker of prostate cancer, acid phosphatase. Additionally, if they administered testosterone to these patients, the acid phosphatase would increase. This built on observations that the enzyme was present in the prostate gland and would go up in patients as they developed metastases, usually in the bones. For this work, Huggins was awarded the Nobel prize in 1966. The use of surgical castration or estrogen administration remained the mainstay of treating metastatic prostate cancer until the introduction of leuprolide in the early 1980’s. I had the extraordinary opportunity to participate in those trials, which we published in 1984. We compared leuprolide to DES, an oral form of estrogen that works on the same endocrine axis as leuprolide, causing the pituitary gland signaling hormone, LH to drop, and subsequently the testicles stop making testosterone. Leuprolide worked as well as DES, but oral estrogen is dangerous – leading to blood clots and increased risk for heart attacks or strokes. Thus, leuprolide (and other GnRH analogs…including the recently approved oral GnRH antagonist, relugolix) became the standard for ADT therapy of prostate cancer.

But estrogen still works. In fact, it may have some significant advantages over surgical castration or GnRH therapy. Our team found that DES could still produce meaningful responses in patients with rising PSA’s who had failed GnRH even though we did see blood clots. But, you can also give estrogen via transdermal patches which avoids many of the problems of oral DES. This week, the PATCH trial program in the UK reported the safety results of using estradiol patches (E) to treat prostate cancer patients compared to GnRH agonists. The ability to produce therapeutic (castrate level) testosterone was the same, but the E treated patients had lower cholesterols, lower blood pressure, less diabetic tendencies, and far fewer hot flushes. Previous study analyses have shown that E is better for bone health with no calcium loss. The only thing that was worse was breast enlargement (gynecomastia) which was seen in 86% of E patients compared to 38% in the GnRH agonist patients. To some extent, gynecomastia can be treated by radiating the breast tissue. The efficacy of E in treating the prostate cancer in these patients will be reported in 2023 and 2024. The cost of E treatment (4x .025mg/24h patches every 3.5 days) is about $62/week ($750/3 months) which is definitely less than any of the GnRH agonists or antagonists. It will be terrific if this “old fashioned” treatment can again join the treatment options for men with advanced prostate cancer. I think it would also be reasonable to try in patients who are failing the newer second generation agents before trying the more expensive/complicated/toxic alternatives like taxane chemotherapy or radionuclide agents (Radium 223, Lu177-PSMA, etc.) With PSA monitoring, it should be relatively easy to find patients who benefit from such treatment.

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January 13, 2021 · 7:08 pm

Pills vs Shots for Androgen Deprivation Therapy (ADT)


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My own interest in prostate cancer began with what, in retrospect, seems quaint and naive. When I arrived at the University of Colorado in 1978, as the first board certified medical oncologist, there were very few clinical trials underway. Having trained (at DFCI) with teams of researchers, my philosophy had evolved to the thought that “every patient should be treated on a protocol, and there should be a protocol for every patient”. This idea (in academic centers, at least) is how we make progress in treating cancer. I continue to urge every patient to participate in clinical research whenever possible, recognizing that for reasons of geography, convenience, or eligibility, it may not be possible. Clinicaltrials.gov lists all of the ongoing clinical research trials for patients and physicians, a dramatic advance in keeping everyone informed. You can learn how to use this tool in one of my previous blogs, here.

With few clinical trials going on at our cancer center, I wrote a naive letter to a number of pharmaceutical companies asking if they had any drug development trials that I might participate in. A single company, Abbott, wrote back inviting me to Chicago to discuss “Abbott 43-818”. This drug was an analog of gonadotropin releasing hormone, GnRH, a peptide (10 amino acids in this case) that looks like this: Pyr-{His}{Trp}{Ser}{Tyr}{Gly}{Leu}{Arg}{Pro}{Gly}-NH2. The 43-818 analog came to be known as leuprolide, and I had the opportunity to participate in taking it all the way from the first dose in men to a final clinical trial resulting in its approval as Lupron™. I’ve been caring for prostate cancer patients and doing clinical trials in prostate cancer ever since – fate!

The way Lupron™ works is shown in the figure below. Normally a part of your brain called the hypothalamus (1) releases a “pulse” of GnRH several times/hour. The peptide travels to the pituitary gland (2) and lands on cells called gonadotropins, causing them to release hormones LH and FSH that travel to the gonads (4) where the ovaries release estrogen or the testes release testosterone. Leuprolide interrupts this process by “over stimulating” its receptor on the pituitary cells and they turn off their LH/FSH production. Because of the small and relatively simple peptide sequence 100’s of other analogs have been made, and the molecular interactions with the receptor have been extensively studied. Some are agonists (like leuprolide/Lupron™/Eligard™, or goserelin/Zoladex™ and others are antagonists (degarelix/Firmagon™).

The hypothalamic-pituitary-gonadal axis

After a long research path, an oral antagonist (relugolix/Orgovix™) has now been synthesized, tested, and approved for treating prostate cancer. It is not a peptide, has the advantage of not having to be injected, and may be safer in patients with a cardiac history. The HERO trial evaluated 934 prostate cancer patients, 2/3 of whom received relugolix and 1/3 received leuprolide. As expected (based on the history of antagonists research), relugolix resulted in more rapid reduction in testosterone, faster recovery upon discontinuation, and faster reduction in PSA.

The frequency of the common bothersome side effects, hot flashes and fatigue, was similar. More patients on relugolix (12.2%) had diarrhea than those on leuprolide (6.8%). However, the leuprolide treated patients had more serious cardiovascular events (myocardial infarction, central nervous system hemorrhages and cerebrovascular conditions, or death from any cause), especially if they had a cardiac history. The incidence was 6.2% in the leuprolide group vs. 2.9% in the relugolix group.

All things being equal, use of relugolix would seem to be a superior choice for ADT in prostate cancer patients. However, as usual, “all things” may not be equal. First, while the biology above may seem to favor the antagonist, there are no data on whether this affects survival or time to progression of prostate cancer. The biology of reducing testosterone as the mainstay of treatment has not changed – we are attacking the same target: testosterone stimulation of prostate cancer cells. Indeed, the more rapid recovery of testosterone upon discontinuation of therapy (for example in a patient who receives several months of relugolix in combination with radiotherapy) might result in better quality of life with rapid recovery, but have a higher rate of recurrence due to the shorter overall duration of ADT treatment. Some patients will prefer pills to shots. On the other hand, insurance coverage for injections might be much better than that for an oral medication. The internet reported cost for a month of relugolix is reported to be $2313. The cost for a one month leuprolide dose is around $1700. However, the cost of a myocardial infarction is not insignificant, and thus comparison of one form of treatment vs another is always more complex than it initially seems.

I am writing this because I suspect there will be “news” articles and other advertising efforts for “Orgovyx™” in coming weeks/months and I hope to refer my patients to this article (and all the other ones I write). If a newly diagnosed patient has impending spinal cord compression, or major organ involvement or a history of cardiac disease, I would recommend the antagonist (relugolix/Orgovyx™) over the agonists (like leuprolide/Lupron™/Eligard™ or goserelin/Zoladex™). If a patient is already on one of those agonists, is doing well and has no cardiac history, there is probably no reason to change therapy. For a patient who is about to start therapy, I will discuss the options, and am happy to prescribe either an agonist or antagonist – it may well depend on insurance issues for a given patient. As with the Covid vaccine, the scientific progress in developing a non-peptide, oral agent is a testament to “our” (medical science) phenomenal scientific advances. The cost of such research (dating back at least to 2013 for relugolix) and what represents fair costs to patients or to Medicare and fair reimbursement to the pharma companies remain concerning to me.

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December 20, 2020 · 1:53 pm

Holiday greetings and philosophy


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I want to wish all of you a very Merry Christmas, happy holiday (whichever ones you celebrate or just celebrated) and a safe and vaccinated New Year. And most of all, THANK YOU to the many folks who contributed to my annual Movember Moustache. We again blew the top off my goal, and it makes me abundantly happy to join you in supporting the research into prostate cancer survival and cure.

Second, I urge you to hang in there, wear your masks, and limit the Christmas interactions. We only have a couple of months to go before we are vaccinated if you are in my age bracket, so stay the course!

Finally, I will share the thoughts of my Department of Medicine Chairman, David Schwartz who has put as fine a summary on where we have been and where we need to go as I have seen. I hope you will find it encouraging:

“A number of months ago, I wrote that ‘Science will lead our way out of this crisis.  Basic modeling and infectious disease epidemiology has helped us understand what’s coming, the science of social distancing, clinical trials have identified remdesivir as a promising agent, novel serologic assays will identify the extent of disease in our communities, and vaccine development will provide the cure.  All of this takes investment, and now is not the time to back away from our scientists or our scientific infrastructure.  In fact, now’s the time to double down.  We still have to get through this crisis but rest assured there will be human health challenges in the future, and we need to be ready.’  

Now with the demonstrated importance of social distancing, the improved care of patients with Covid, and the FDA emergency use approvals of the Pfizer and Moderna vaccines, it’s time that we recognize and celebrate the truly remarkable advances in our fight against Covid that have been made since the initial transmission of SARS-CoV-2 in the Huanan Seafood Wholesale Market only one year ago.

·         Social distancing:  The past few weeks have demonstrated the profound effect that social distancing has had on the transmission of the virus.  The story of the coronavirus in America is a compartmentalized one, with different places experiencing different spikes for different reasons at different times.  Fortunately, over the past week in Colorado, there’s been an average of about 3,100 cases per day, a decrease of 28% from the average 2 weeks earlier.  This decrease in cases per day in Colorado is reflected in the census data in our hospitals, and the state-wide hospitalization data with both peaking and slowly going down since the beginning of December.  In contrast, over the past week in the entire U.S., there’s been an average of about 220,000 new cases per day, an increase of 19% from the average 2 weeks earlier.  Continue to wear a mask, practice social distancing, and don’t travel over the holidays.

·         Clinical trials:  Over the past year, well-conducted clinical trials (by many of our investigators) have identified what works and what doesn’t.  Our improved ability to take care of patients with SARS-CoV-2 infection is reflected in the decreased percent of patients requiring ICU care (55% last spring – 40% now) and a decrease in the number of patients in the ICU requiring intubation (90% last spring – 67% now).  Moreover, the survival and re-admission rates continue to improve among our Covid patients.

·         Vaccines:  One year ago, very few people would have predicted that we would be embarking on a vaccination program with two extremely effective vaccines with minimal side effects.  This was not a miracle.  The development of these vaccines were enabled by many scientific accomplishments (bat virology, DNA sequencing, computational biology, and basic science of RNA, proteins and lymphocyte biology to name a few) that have been supported by the federal government, industry, academia, and public-private partnerships.  Investments in science are essential to our future.

I think there are other take home-messages that will continue to strengthen the scientific programs on our campus:

·         Team science and scientific partnerships are critical to combining clinical insights with cutting–edge research.  Collaborations and social networking will improve the efficiency of research.  We need to foster these interactions.

·         Public-private partnerships (like the one between the NIH and Moderna) can lead to powerful advances and need to be nurtured.

·         Our nation has to place a higher value on science.  Part of this involves public education and we’ve got some real opportunities with our patients.  However, we should also do everything possible to help Congress recognize the sad lessons learned from the ways science has been pushed aside during the pandemic, and strongly advocate to substantially increase the federal research budget.”

To all of you who subscribe to this blog, I thank you for your interest, ideas for topics, and your support for the physicians, nurses, staffs and researchers who have made it possible for all of us to live longer and healthier lives than any generation in history. It has been an incredible journey for most of us and in spite of the 2020 “downer” we have much to be thankful for. Keep exercising and my best wishes for the New Year!

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November 30, 2020 · 11:15 am

Epigenetics


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One of our faithful readers suggested this topic. My first introduction to the concept of epigenetics may have been in a lecture that the late Don Coffey gave at a course I helped organize at the Given Institute in Aspen which still goes on today. Don was a pied piper to hundreds of students at all levels at Johns Hopkins, and on his first visit to the course told them about arriving late at the Denver airport, driving his rental car too fast over Vail pass, then exiting and hiding under a bridge while a State Patrol car zoomed over him, and getting back on the road to make it to Aspen just in time. Not a bad way to endear yourself to some younger physicians in training!

His signature illustrative story was that of the fertilized hen’s egg. There it sits, with all the information needed to make a full chicken encoded in the DNA, but nothing happens until it is put in an incubator and the temperature rises. Only then does the machinery kick in to go from a single cell to billions of cells with everything from feathers to an intestinal tract. “How does that happen?”, he would ask, and then proceed to talk about how the DNA is wrapped around histones as shown in the following illustration:

Dr. Coffey would then show pictures of DNA in prostate cancer cells, some of which was compactly wound around the histone proteins (and therefore inactive) and some of which was “open for business” with long loops of DNA strands sticking out from a chromosome. I love the simplicity of this illustration, because it demonstrates how not only temperature can influence the long string of base pairs that otherwise are the deceptively simple ATCGTCCATA… code, but also begins to explain how environmental factors, drugs, aging, and diet can change gene expression. My hiking friend, who is somewhat of a eugenics devotee, thinks mankind will evolve to [his view of] perfection by using CRISPR to modify just the DNA sequence and change everything from physiognomy to behavior. I, of course, disagree based on epigenetics. A woman in her first trimester who eats too much broccoli one evening might well affect her child’s math score by 1/10 of a point…

But back to prostate cancer! As shown in the above figure, one of the common ways genes and their expression is modified is through methylation. The chemistry is shown in this figure and a complete article on DNA methylation from Wikipedia is here.

This image shows a DNA molecule that is methylated on both strands on the center cytosine. DNA methylation plays an important role for epigenetic gene regulation in development and cancer. [Details: The picture shows the crystal structure of a short DNA helix with sequence “accgcCGgcgcc”, which is methylated on both strands at the center cytosine. 

These methylation changes are frequently found in what are known as CpG islands, or areas of the genome that are rich in Cytosine Guanine base pairs, and particularly in the so called “promoter regions” upstream from the gene itself that control whether the gene is “active” or not. In prostate cancer, methylation of an enzyme called GSTP1 was one of the first methylation markers that became useful in detecting prostate cancer. If a man with a highly suspicious rise in PSA was biopsied and there was no cancer found, if the biopsy of the “normal” tissue next to true cancer was analyzed and methylation of GSTP1 was found, it was highly predictive that real cancer was present but just missed. As time went on, many other genes with hypermethylation changes were found, and panels of such genes could be used to detect prostate cancer cells in the urine, potentially replacing invasive biopsies. More recently, utilizing advanced techniques to search for methylation patterns in the whole genome, it has been possible to find markers (probes) for genes (see this article) which are differentially methylated in prostate cancer and have dramatic prognostic significance. Here is one such example showing that depending on which form (allele) of a gene called ATP2A3 (that can be methylated or not) you inherit, it can affect your survival.

The homozygous alternative genotype of a haplotype on chromosome 17, associated with methylation of ATP2A3, gives a survival advantage. HR and P values are from the CoxPH model.

Although much of the article from which I copied that figure is way (WAY) over my head, the point of understanding epigenetics is that prostate cancer is much more complicated than just a mutation or two in some cancer causing genes. The expression of a myriad of other genes that can be controlled by methylation or other epigenetic processes can play a major role in what happens to us. As it turns out, this week’s NEJM has an article specifically related to the epigenetics of prostate cancer as it evolves from localized to metastatic. Here is the key illustrative figure and accompanying explanation.

Figure 2. Epigenetic Regression with Clinical Progression of Prostate Cancer. Pomerantz and colleagues4 describe epigenomic patterns that occur in the transitions from the normal human prostate gland to organ-confined prostate cancer to metastatic castration-resistant prostate cancer, with their findings regarding metastasis relying largely on patient-derived tumor xenograft models. Sites of androgen-receptor binding in the genome have been associated with this transition from normal prostate gland to metastatic disease. Such binding sites are “premarked” by the transcription factors HOXB13 and FOXA1. Also, the researchers found that sites that are specific to metastatic castration-resistant prostate cancer correspond with sites in the open chromatin state in the normal prostate gland and in organ-confined prostate cancer, which indicates a lower barrier to reprogramming to a metastatic state. The epigenome (H3K27 acetylation) pattern in prostate cancer metastasis was similar to that in fetal (but not adult) prostate cells. A limitation of the study is that it does not include an analysis of circulating tumor cells or metastatic castration-sensitive prostate cancers.

As this story unfolds, “precision medicine” will become a way to individualize prostate cancer treatment. However… the heterogeneity of prostate cancer metastases will remain a major challenge in the practical application of such knowledge. Meanwhile, if you haven’t already supported prostate cancer research through my Movember effort, feel free to wander over to my website and make a contribution – and THANKS to all of you who helped me reach my goal!

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