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!


Filed under General Prostate Cancer Issues, Uncategorized

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!


Filed under Uncategorized

Yay…Movember is here. Let’s kick Pca

Hi friends and relatives (those who will admit it…),

This Movember, I’ve committed my upper lip to help change the face of men’s health by growing a moustache, now I need your support at Movember Foundation is the leading global organization committed to changing the face of men’s health. I’m passionate about this cause because too many men are dying unnecessarily from prostate cancer. In 2014, more than 233,000 men will be diagnosed with prostate cancer. Even better, join our team and donate to yourself and invite your friends/family to the cause! Our team is here:

 The Movember Foundation is working tirelessly with an urgent goal in mind: accelerating breakthroughs in prostate cancer research that will benefit patients and their families. Movember is achieving this with the formation of the largest, global alliance of prostate cancer researchers and clinical specialists, who are tackling the toughest prostate cancer challenges. I had the privilege of hearing the updates on the research they have been sponsoring last week at the PCF retreat. More progress in the last 5 years than in the previous 25. Take a look there for updates/posts yourself!

I need your support to fund this important work. Together, we can create a world where no man dies of prostate cancer.

You can donate by:

- Donating online at (and follow the pathetic growth of my not-so-manly moustache…)

- Writing a check to ‘Movember’, referencing my registration ID: 5798901 and mailing it to:  Movember, P.O. Box 1595, Culver City, CA 90232

You can learn more about the important work and impact Movember is having at:’s a lot riding on this moustache, thank you for your support!

 Mo Bro Michael Glode

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Filed under General Prostate Cancer Issues

The robot vs the surgeon.

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I have previously blogged on the issues surrounding robotic prostatectomy. Recently I was asked by my professional society, ASCO (the American Society of Clinical Oncology) to provide commentary on two experts “debating” the pros and cons of open (tradiational) prostatectomy vs. the robotically assisted laproscopic approach. Rather than give a long, repetitive blog to you, I am just going to have you click on THIS LINK to read the post.

The issue is largely going away because of the dominance of the robot in clinical practice, but I thought that the experts did a great job explaining their positions.


Filed under Uncategorized

Statins and prostate cancer

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The use of statins to control dyslipidemia is now over 20 years old and supported for patients with coronary artery disease by the landmark Scandanavian Simvastatin Survival Study published in 1994. That study demonstrated a significant reduction in the rate of myocardial infarction and death among treated patients and remarkable safety. Subsequently numerous trials demonstrated their efficacy and safety in the cardiovascular arena even among patients with relatively normal lipid profiles and found a wide variety of other “off target” effects of statins which were originally designed to inhibit HMG-CoA reductase, a key enzyme in the regulation of cholesterol. For example the JUPITER trial highlighted the importance of CRP, a marker of inflammation as a possible additional mechanism of action.

Fortunately, many of the “off target effects” of the statins also have the ability to suppress cancer development, some of which may relate to the evolving understanding of insulin resistance and insulin as a growth factor for prostate cancer. Dozens of articles have been published on the efficacy of statins to reduce the incidence of a wider variety of cancers, including (but not limited to) colon, breast, esophageal, gastric, and melanoma because their use is so common in the population and both cancer and heart disease are common to the aging process. The studies are often confounded by “what else” patients might have been doing (exercise, low fat diets, taking NSAIDS, finasteride, dutasteride, etc), but in general it is likely that statin use is beneficial in prevention and perhaps in prolongation of survival among patients with prostate cancer. In one of the larger articles demonstrating this effect, Yu et. al. studied 11,772 men from the UK who were newly diagnosed with non-metastatic prostate cancer between 1998 and 2009. They published these conclusions in the Journal of Clinical Oncology last year:

“During a mean follow-up time of 4.4 years (standard deviation, 2.9 years), 3,499 deaths occurred, including 1,791 from prostate cancer. Postdiagnostic use of statins was associated with a decreased risk of prostate cancer mortality (HR, 0.76; 95% CI, 0.66 to 0.88) and all-cause mortality (HR, 0.86; 95% CI, 0.78 to 0.95). These decreased risks of prostate cancer mortality and all-cause mortality were more pronounced in patients who also used statins before diagnosis (HR, 0.55; 95% CI, 0.41 to 0.74; and HR, 0.66; 95% CI, 0.53 to 0.81, respectively), with weaker effects in patients who initiated the treatment only after diagnosis (HR, 0.82; 95% CI, 0.71 to 0.96; and HR, 0.91; 95% CI, 0.82 to 1.01, respectively).”

A very balanced editorial accompanied this publication reviewing the many similar articles and came to the cautious conclusion that “the current data may be sufficient to sway some clinical decisions toward statin use for men who are on the borderline for cardiovascular disease prevention.” I would certainly concur with this opinion, and if you have family members at risk for prostate cancer, it would seem prudent for them to have their lipid profiles tested and (given the other potential benefits and low risks for statin use) have them discuss starting statins if they have not already done so. Adding statin “therapy” after prostate cancer is diagnosed is probably of little harm, but as with metformin, much less proven as an interventional strategy.


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What is going to kill me? – the cloudy crystal ball

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With an intense focus on prostate cancer, it is easy to overlook the reality of other causes of death or disability in making decisions about therapy. An example of this issue is the proliferation of molecular tests that have been validated to separate patients with “intermediate risk”, or “low risk” into “even lower” or “even higher” risk disease categories using a number of different gene expression profiles on the tumor or biopsy material. For example, Genomic Health offers the Oncotype Dx test that provides a “Genomic Prostate Score” that gives a patient who (based on clinical criteria such as PSA and number of biopsy cores positive) falls into a low or intermediate risk category another lab value (GPS) that can potentially be useful in making a decision about treatment. GenomeDx has a test that can evaluate high risk men after prostatectomy to more accurately predict metastatic disease at 5 years. There is a very balanced article on the challenges of using these tests (which are a potential step forward to be sure) in the real world of the clinic here.

However, in all of the excitement and marketing of these and other tests, a couple of key facts are often overlooked (and may be much more important in decision making). Prostate cancer is generally a slow disease anyway. Competing mortality looms large as patients get older. And most importantly, there are validated ways to put the “whole patient” into the picture before ordering these tests, whether they be a PSA, biopsy, or molecular analysis. The Charlson comorbidity index can be extremely useful in predicting survival and is barely ever mentioned in the molecular analysis literature/reports. It is a simple yes/no answer to whether a patient has any of these 12 conditions: diabetes, bleeding gastrointestinal ulcer, chronic lung disease, congestive heart failure, stroke, myocardial infarction, angina or chest pain, cirrhosis or liver disease, arthritis, inflammatory bowel disease, hypertension, and depression. In a lovely article published last year, the use of this analysis in relationship to prostate cancer mortality gave a vivid picture of prostate cancer mortality in the larger setting of 3533 men with prostate cancer. A snapshot of their data looks like this:

Screen Shot 2014-06-19 at 9.15.54 AM

Very often, the comorbid conditions lead to death from another cause. In my opinion (and in my practice), we too often ignore our ability to quantify the risk of dying from “something else” when we focus so intensely on the PSA or other tests in counseling patients about what to do. It is also true that patient perception of test results can vary dramatically. One patient with a “GPS score” of 10 might be reassured, while another will perceive it as “not low enough” and opt for aggressive treatment rather than observation. To some extent this exposes the fallacy of “we need to separate the issue of treatment from that of diagnosis” thinking. Until the crystal ball becomes crystal clear, management of prostate cancer will remain challenging and requires the kind of wholistic thinking that is often better done by primary care physicians or public health professionals than by prostate cancer docs, or their patients.


Filed under General Prostate Cancer Issues

Practice changing results….chemotherapy up front.

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Adding 6 cycles of docetaxel at the outset of hormonal therapy for prostate cancer has been shown to improve survival, especially in men with a high burden of disease. The much anticipated report was presented in detail today at the ASCO annual meeting. Those of you who have followed this blog will remember that I previously highlighted the CHAARTED trial when the trial was stopped prematurely because of the positive result.

The first author, Chris Sweeney, is a good friend and led the study in which several of our patients here in Denver were participants. Thanks guys !

This study randomized 790 men who presented with metastatic prostate cancer and who had never received hormone therapy (ADT) to receive ADT alone (393) vs ADT plus chemothrapy with docetaxel (397) starting up front at the time the ADT was started.  In patients with high volume disease, defined as those men with visceral metastases or >3 skeletal mets including one beyond the pelvis and spine, there was an improvement of 17 months in overall survival from 33 months to 49 months with a p value of <.0006 for significance between the two arms of the trial. The men with lower volume of metastases are also doing better, but the curves for the two treatment arms have not met significance. There was reasonable balance in age, race, psa values, etcetera between the arms. A key point is that 3/4 of the men initially treated with ADT alone went on to receive docetaxel at the time of progressive disease, meaning that this trial can reasonably be considered to reflect a “pay me now or pay me later” with docetaxel toxicity, and the men who were on the “pay me now” arm had the most benefit from the toxicity of the chemotherapy. There was good balance between the arms in terms of the number of men who received others of the newer treatments (abiraterone, enzalutamide, sipuleucel-T).

For prostate cancer, this is akin to the studies of using chemotherapy “up front” in the adjuvant setting that really got medical oncology going in the early 1970’s in women with breast cancer. It opens the door to the study of using aggressive multimodality treatment including the newer hormonal agents, and possibly vaccines, in men with high risk disease at the very outset of their therapy, which should be the next studies. The problems with designing such studies is the very long period of time it takes to get answers. CHAARTED was opened in 2006 and only now, 8 years later, do we have a result. The time could be dramatically shortened if more men would be placed on clinical trials. 1000’s of men were treated with same old same old treatment during the time we worked on CHAARTED. If 50% of them would have been put on this trial in the first two years, we could have had this result about 4 years earlier. Since that takes a major change in how medicine is practiced in the US, don’t hold your breath.


Filed under General Prostate Cancer Issues