Tag Archives: prostate research

No pain, no gain?


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One of my patients last week had a heartfelt discussion regarding the survival benefit of ADT vs his quality of life. He enjoys body building and showed me some pretty dramatic pictures of himself during his last ADT cycle (on intermittent therapy) versus now, when he had been off treatment for ~6-9 months. Added to his concern was his decline in libido and sexual function during ADT, a common complaint especially among younger patients. The question of quality vs quantity of life was,of course, utmost on his mind.

Starting from the initial diagnosis, every (maybe that should be every !!) prostate cancer patient will experience a decrement in quality of life. Those who elect “watchful waiting” will nevertheless experience anxiety regarding the shadow of CANCER following their footsteps. Sure, you can put it out of your mind, but turn around and there it is, like the neighbor’s unwanted cat stalking you. Then there is the anxiety over what the next PSA will be. And if on active surveillance, what will that next biopsy show?? These issues are both real, disturbing, and often under-appreciated in the discussions surrounding screening…”we should still be screening, but not treat the men who don’t need it…” Really? What about the 80% of men who die at age 90 with prostate cancer at autopsy who never had to deal with the shadow? (The inevitable counter-argument is, “yes, and what about those who had early detection of a high grade cancer whose life was saved?”)

We also tend to ignore the impact of competing mortality in our discussions. “Sure you had a stent placed last year, and you already survived that small colon cancer, so why wouldn’t we be aggressive in treating this new problem?” Dr. Sartor provided an elegant discussion of this in an editorial on the PIVOT trial you can read here. Whatever the flaws in that study, it remains clear that we are not very good at predicting the non-prostate cancer “future” for our patients, and the older you are, the thinner the ice gets regardless of how many marathons you run.

When patients choose one form of primary treatment vs another, they are weighing the different side effect profiles of surgery or radiation as much as which is “most effective”. I often give patients a copy of this article from NEJM and encourage them to spend some time looking at the graphics in Figure 1 to get some idea of what they will face in the way of side effects from treatment. As any honest physician would tell them, treatment will involve side effects, some permanent, in the best of circumstances.

In the setting of more advanced disease, for example a patient who presents with metastases outside the pelvis, the recent CHAARTED and STAMPEDE trials both suggest an advantage to the earlier use of docetaxel chemotherapy in combination with ADT as opposed to ADT alone. These data suggest that “pay me now or pay me later” analysis favors the “pay me now” approach in terms of overall survival. But at what price for quality of life? Fortunately most chemotherapy side effects are reversible, but distinctly unpleasant, potentially making the equation something like “4 months of misery to provide 14 months of longer life….not all of which will be great anyway”.

Even in the very advanced setting, there is some evidence that greater toxicity results in improved survival. A recent analysis of the TROPIC trial of cabazitaxel suggested that the patients who had the most “toxic response” in terms of dropping their neutrophil count benefited the most in terms of overall survival.

While all of this seems incredibly negative (for which I apologize), the history of oncology as a field has been the incremental improvement in survival AND the development of newer treatments that provide such advances with diminishing toxicity. Pediatric leukemia, as discussed extensively in “The Emperor of All Maladies” is a great example of how pioneering patients and physicians worked together to find cures and reduce side effects. We may only be at the beginning of such achievement in prostate cancer, but with the advent of the newer hormonal and imaging agents, increasingly sophisticated surgery and radiation, vaccines and immunotherapy, and even the chemotherapies now available, we have  no doubt reached the end of the beginning. Onward!

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Olaparib for resistant prostate cancer


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In what is the first (and hopefully one of many) example of using modern genomic methods to match treatments to the molecular defects in prostate cancer, the FDA has just granted “breakthrough designation” to olaparib, a drug made by AstraZeneca. This followed a publication in the NEJM with nearly as many authors as patients, illustrating the power of team science and international collaboration.

Cancer cells develop numerous mutations that provide them with the ability to divide, metastasize, escape immune surveillance and so forth. One of the drivers of this mutation cascade is genetic instability, in part due to the accumulation of mutations that keep the cells from correcting DNA alterations. These mutations in DNA-repair enzymes can leave the cancer susceptible to additional inhibitors of DNA repair, one of which is PARP, an enzyme found in the nucleus that detects DNA strand breaks and initiates repair. When olaparib interferes with this enzyme, cells can become so genetically unstable they die.

In the TOPARP-A trial, 50 patients who had castrate resistant prostate cancer and had progressed on second generation anti-androgen treatment and docetaxel were given olaparib. 16 of 49 evaluable patients responded, however the exciting finding was that because these patients participated in the clinical trial and allowed the investigators to biopsy their tumors, it was possible to relate response to the presence of defects in the DNA repair genes. For this subgroup, 14 of 16 responded, indicating that using the repair defects as a biomarker you could predict high response rates, while at the same time, patients without such genetic defects had a much lower response rate (2/33). There is an excellent video that illustrates the results accompanying the publication that you can find by clicking here.

Although this is terrific news for prostate cancer patients, it brings a number of challenges. Testing for genetic mutations is a growing (and somewhat expensive) process. When compared to giving patients a drug that predictably won’t work, however, it can be very cost effective. Second, when you biopsy a tumor, the results can vary depending on where you biopsy as I discussed in this previous blog. “Liquid biopsies” of circulating DNA or tumor cells may provide some help in meeting this challenge.  Third, responses to targeted therapies such as olaparib tend to be rather short-lived, as the cancer cells continue to mutate to find ways around the new agent. The hope would be that combining a targeted treatment like olaparib with an immune approach might bring more prolonged responses. Finally, we must find a way to deal with the extraordinary costs of the new oncology drugs. The actual cost of olaparib is $13,440/month according to this article in the ASCO post. I have previously opined on this issue and invite you to join the discussion by clicking here.

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Sensational results, 4-MU, Viruses, and “the drive-by media”


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An intriguing part of writing this blog is how much I learn from my patients. It also turns out that I learn ABOUT my patients. I suppose nothing should surprise me about this in the digital age, where presumably all of you can find my address, social security number and probably what brand of oatmeal I like ! (I’ll save you some time there, try McCanns Steel Cut Irish Oatmeal, it’s terrific…). For the past month or so, one after another has come in with the question, “So, what do you think about 4-MU?” or “Did you hear about poliovirus killing cancer?” Actually, I have heard next to nothing about either, but of course I was intrigued as to where my patients get their information.

Starting with the 4-MU story, it seems it was featured on that bastion of “fair and balanced news,” FOX. I sincerely hope that is not the primary source for your news, and that you don’t subscribe exclusively to a certain talk show host who calls everybody but himself the “drive-by media”. If you want serious journalism, I’d suggest the NYT, WSJ, and NPR for a pretty good balance of real news. None of them carried the two stories I’m going to go over here. Further, if you ever hear of a story with interest in medicine, I suggest you go immediately to Google Scholar, which is absolutely wonderful at finding abstracts, patents, and journal articles on almost anything in medicine. And if you want to know if a novel treatment in development is available in your area or anywhere else, for that matter, do your search at ClinicalTrials.gov.

Well, using combinations of all of the above to learn about 4-MU, (which stands for 4-methylumbelliferone) I found that FOX decided to sensationalize a mouse study published by some University of Miami investigators. 4-MU turns out to inhibit synthesis of hyaluronic acid, a major component of synovial fluid and the “goo” or intracellular matrix. It has been studied in the past to inhibit some bacterial and viral replication, and indeed there is even a clinical trial with 4-MU listed as going on in chronic hepatitis. The Miami researchers found that in mouse models 4-MU inhibited prostate cancer metastases, which gained excitement because it is supposedly a non-toxic supplement. While I try to keep an open mind, there is a long history of various natural products working in mouse models that then have little or no activity in the real world of human cancer. We, ourselves, discovered that acai juice and the milk thistle derived molecule, silibinin, had minimal/no activity in prostate cancer, in spite of promising results in animals. My judgment regarding 4-MU is that it would indeed be of interest to study in human prostate cancer, and hopefully it would work, but until such a trial is done, I would not recommend taking it if you find a supplier somewhere on the Internet or similar.

The poliovirus story is a bit more complicated. It gained patient attention via a 60 minutes presentation.  Many tumors, including the highly lethal glioblastoma brain tumors, have receptors on their cell surface for the virus. Through very elegant and complex recombinant DNA technology, investigators at Duke University engineered a novel virus that could induce death in the brain tumors after direct injection. In an ongoing Phase I clinical trial, they are seeing dramatic responses after direct injection of the tumors in the brain, in part because of a “violent” immune response. The key here, however, is direct injection. It may be possible to build on this, but direct injection of oncolytic viruses into head and neck cancers, lung cancers, and even prostate cancers in the past have not had the desired results. Moreover, what we really want, is some sort of virus that a) can seek out every metastatic cell in the body [brain tumors seldom metastasize, but kill people by local growth], and b) produce that immune response after infection. I have written elsewhere about the promise of the immune checkpoint inhibitors, and I encourage you to go to my blog site and read about those ongoing efforts. Meanwhile, I hope that the search strategies I have outlined in this blog will help you do your own research to answer the question, “Doc, have you ever heard????….”

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The billionaire cancer researcher


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Several patients/friends told me this week about the 60 Minutes piece highlighting the ongoing efforts of Patrick Soon-Shiong, a surgeon who was involved in the development of abraxane and has become worth $11B as a result. So I did my duty and watched on the Internet tonight and will share my thoughts with you loyal followers. Let it first be said that the optimism in this video is compelling, and for the most part based on science that has been going on for the past decade or so in labs all over the country. The 60 Minutes team working with Dr. Soon-Shiong highlighted in a visually compelling, and mostly understandable way, the progress that is being made using the latest technology and understanding of cancer biology. I will highlight this as follows: 1) massive computer technology and sequencing advances allow “all” of the mutations that characterize a cancer cell to be displayed. 2) Drug development to attack vulnerable biologic pathways within cancer cells is accelerating. 3) The possibility of finding the gene mutations driving these cells by looking at circulating tumor cells portends a [mostly] promising way of sampling what is going on within a patient, yet not having to biopsy the tumors. 4) The recent breakthroughs in enhancing immune responses to tumors by shutting down the innate immune checkpoint controls appears to offer great promise for “wiping out” residual/resistant tumor cells.

With that summary, let me urge anyone who watches/watched the video to pay close attention to my good friend, Derek Raghavan’s commentary. Derek is one of the most insightful and honest translational medical scientists I know. In essence, he points out that although Dr Soon-Shhiong is applying an “all of the above” approach to the attack on cancer, there will still be enormous amounts of work to be done and thereby hints at the problem I have  with the video – overselling hype/hope is a specialty of the media. Presenting the single patient with pancreatic cancer who is doing well is an example of this focus on the “sizzle and not the steak” approach. I take nothing away from what a billion dollars can do to pull the existing technologies together and applaud Dr. Soon-Shiong’s efforts. As a matter of fact, one of the techniques he touches on, using low continuous doses of chemotherapy, is something we may have been the first to try in prostate cancer several years ago and published here.

So what are the cautionary issues? 1) The sheer number of mutations found in most cancers (and perhaps especially prostate cancer where the term “shredding of the genome” has been used, make attacking ALL of the pathways at once nearly impossible.  If even one cell can further mutate in the face of having, say 6 or 7 drugs being given to shut down the mutations, it will survive to become the dominant and lethal metastatic problem. This is layered onto the challenge of using “all 6 drugs” together, which will more than likely compound the toxicities to the host when compared to using one of them at the optimal dose. 2) Tumor heterogeneity. In an incredible tour-de-force, a team of scientists at the Cancer Research UK London Research Institute  did whole genome analysis of the original kidney cancer in four patients as well as in their metastases. The graphic of how the research was done is shown here:

Screen Shot 2014-12-10 at 10.23.28 PM

Each spot in the original tumor as well as each metastasis had a somewhat unique set of mutations. Thus “personalized medicine”, the favorite buzzword of the moment in medicine, has a huge challenge in cancer, since there might be different combinations of drugs required for each metastatic site in some patients. The same might apply even for the evaluation of individual circulating tumor cells of course, which is now possible. A cell coming into the research syringe at one time might reflect a tumor deposit in one area, while the next cell isolated could be coming from somewhere else. 3) The excitement over using the most clever of the immune approaches, including the checkpoint inhibitors and the CART cell approach have significant challenges, either because of unleashing autoimmunity, or the very high costs of manipulating each individual patient’s T-cells in order to come up with the autologous cancer-fighting cell treatment.

So, here’s to the optimism and billionaire strategies, and we all hope it moves forward quickly and successfully. And here’s to 60 Minutes for highlighting the amazing biology and progress that is being made. Hope is one of the keystones of human progress, whether it is landing on Mars or repairing a broken relationship. Love and hope are what make life worth living. May your holiday celebrations be filled with both!

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Deep in the weeds. “Doc, is there anything new?”


How to answer this VERY common question is a pretty daunting task. Last week I was at the PCF Foundation annual scientific retreat. This is the ultimate place to hear about new science in prostate cancer, and the incredible progress being made. That said, distilling even one of the many lectures given by leaders in the field is challenging. If I were writing for the National Enquirer, I would have enough notes to write at least a year’s worth of “CANCER BREAKTHROUGH PROMISES PROSTATE CANCER CURE” articles.

So let me just wander into the weeds a bit from only two such lectures . Karen Knudson is one of the best prostate cancer researchers on the planet at this point. She works effectively with clinicians and basic scientists alike on a variety of projects that ultimately yield insights into what controls prostate cancer cell biology. Her lecture this year was on DNA repair targets. (Disclaimer: It is very much beyond my area of expertise to try and cover DNA repair at a sophisticated level, but there is an excellent article dealing with this in the New England Journal this week.) So here we go, weed hunters.

The DNA in each cell is not the long strand of double helix you are used to seeing. Rather, it is intimately wound up with proteins that give it structures looking like a thread wound around a protein ball, then these are further formed into bundles that aggregate and ultimately form the chromosome pictures you find in biology textbooks. The nuclear proteins that are part of this process, in turn, are not only structural, but also contribute to how the Androgen Receptor (AR) binds to specific locations on the DNA and leads to cell growth, turning on the gene that makes PSA and so forth. As you know, AR biology insights led to abiraterone (Zytiga™) and enzalutamide (Xtandi™)

OK, if you have followed this far, get ready for more complexity. The nuclear proteins can all be modified in their functions (helping to initiate the replication of DNA, peeling off the RNA that will go to the cytoplasm to code for proteins, changing the structure of the chromosomes, etc) by enzymes that change the proteins themselves (their shape, charge, function). There are several such modifications, but common ones consist of adding CH3 (methyl) molecules to specific spots on the proteins, or COCH3 (acetyl) molecules. These changes can have dramatic effects on which genes are expressed in which tissues and there is an easy to read overview called the histone code in Wikipedia. (please, please click on that link and read the paragraph on its complexity to get a feel for the research described below)

Honestly, Glode, get to the point….(and I sincerely hope you took a look at some of the links I put in above to make the structures and details more available)

OK, so to make it more relevant to Pca, an important modifier that has explicit functions in cancer is a protein called PARP1. This is an enzyme that modifies the nuclear proteins by a process called ADP ribosylation and adds simple molecules called ADP-ribose to various proteins (including itself) for modifying function. It turns out that PARP1 binds at sites similar to the place where the Androgen Receptor binds in the DNA and also changes other other proteins called DNAPKs that help to repair DNA. The DNAPKs are dramatically over expressed in castrate resistant prostate cancer, and if you inhibit them, you can suppress metastases from forming. Inhibitors of PARP1 and inhibitors of DNAPKs are under intense study as possible therapeutics for prostate (and other) cancers. One such example is cc-115 that is being studied by Celgene, but there are others.

 

So if you got this far, you have successfully navigated exactly 35 minutes of notes from Karen and another colleague from Celgene, Kristen Hege. And remember, the program went on for a day and a half with me furiously writing notes. It was like drinking from a fire hose, but the net result is this answer to the question, “Anything new?” OMG, “YES” and thanks to the science community for working so hard on unraveling what we need to know about how cancer operates!

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Amazing genetics and personalized medicine


I have been a bit concerned for some time regarding the hype surrounding “personalized medicine” as it relates to cancer. The concern arises from the excitement generated when a novel mutation can be targeted in a specific subgroup of cancer patients with astonishing results. The media goes wild. A good example of this is the BRAF mutation in melanoma. The V600E mutation found in 40-60% of patients with melanoma can be targeted with a drug (vemurafenib) that inhibits this activated cancer causing enzyme. The results can be astonishing, including apparently complete remissions in a disease that only 5 years ago was always fatal when metastatic. However, less well “advertised” is the fact that in most cases, the duration of such responses is quite short (median time to progression with BRAF inhibitors seems to be in the 6 month range). You can read a nice article on this story here. The personalized medicine aspect is that there is no reason to treat with the expensive drug if you don’t find the mutation. That’s the good news of personalized medicine. The bad news is that for cancer, heterogeneity is the achilles heel of this approach. If even one cell doesn’t have the target, it will survive…and/or cells that do have the target have enough genetic instability to get around the block in short order.

Now comes a fascinating study from the outstanding Hopkins investigators who looked at prostate cancer in a single patient who was diagnosed with prostate cancer at age 47. In the beginning he had a lymph node that was involved and he received surgery, androgen ablation, localized radiation and eventually chemotherapy and vaccine therapy. He succumbed to widespread metastases 17 years later at age 64. By doing deep genetic analysis of the primary tumor, the researchers were able to identify the source of the metastases. Surprisingly, the lethal metastatic disease originated in a small part of the primary tumor that was low grade, Gleason pattern 3, not the more aggressive, larger volume tumor elsewhere. While this is the first such study I am aware of in prostate cancer, similar studies in a few patients with renal cancer were reported last year.

So, for personalized medicine, the situation is either a cup half-full or half-empty. If you are an optimist, you hope that the majority of cancer cells in a patient can be targeted with a “driver mutation” like the BRAF mutation, and that when all of the susceptible cells have died off, the immune system might be stimulated to take over with a vaccine, or one of the exciting drugs that potentiate an immune response by knocking down the control arm of the immune system (PD-1 inhibitors, ipilumimab, etc.) and that the last cell will be eliminated before genetic instability gives the cancer the upper hand. If you are on the “half-empty” side, you contemplate that the human genome has evolved over millions of years to be remarkably adaptable to everything from volcano sulfuric gases to solar radiation, and that without such adaptability we might not be here at all. In this scenario, it seems unlikely that we will easily conquer the myriad of survival pathways that got us here by just attacking one of them. And…which one to attack may depend on which biopsy site you look at.

I haven’t decided which philosophic point of view I favor. The incredible progress made in treating HIV by attacking multiple pathways and converting HIV-AIDS to a chronic illness, much like diabetes, provides hope. So does the fact that the Hopkins patient lived 17 years thanks to the progress made in treating prostate cancer. As I often remind my patients, “if you die of a heart attack, we will count that as a cure of your prostate cancer”. May we all live in a healthy condition until our time comes!

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Active Surveillance – NIH draft statement


Not to put too many blogs up this week, but  a very well balanced article was just published and includes input from my friend Lori Klotz, whose articles have been at the forefront of doing active surveillance. He tried to get an international trial going that would provide some definitive evidence that this is a reasonable alternative. In the trial, men with low-volume Gleason 6 disease were asked if they would sign up to be randomized between immediate therapy versus going on an active surveillance program. We had the protocol open for about two years and could only find 1 or 2 men willing to participate. When you read THIS ARTICLE, you will see that the study was really important, since a significant portion of men go on to get treatment anyway, and that some studies suggest lower survival with this approach. On the other hand, those being watched do not suffer the side effects of definitive therapy. As with screening, there will be no “final answer”. However I really like this statement as an informational piece that I can give patients who are considering this approach. We also still offer targeted focal therapy at our institution as a possible “in between” treatment option – an interesting approach that is still very early in terms of knowing the long term consequences of this treatment. Mike Landess took this approach and has made a nice video blog of his experience. One of the major unanswered questions in all of this is what the optimal formula for followup should be. For example, PSA’s every 3 months, or should it be more often? Should you initiate treatment based on some absolute number, or a change in the doubling time? Should you biopsy every 2 years, or should it be 18 months? What about doing mapping biopsy on everyone who wants to consider active surveillance? So many questions and so little time !

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