Tag Archives: genome

Ho, Ho, Hox

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Fruit flies are a fascinating scientific resource to consider if you can get beyond your annoyance when they appear in one of those lovely boxes of ripe fruit you receive from a relative this time of year. (Just be thankful it wasn’t fruitCAKE!). For some great reading on the topic, I highly recommend a book, “Time, Love, and Memory“, the story of Seymour Benzer and how his graduate students figured out how different genes are involved in these creatures’ sense of time, or how they do their mating dance or remember whether they shouldn’t put their little leg down into a beaker and get a shock.

As with their behavior, there are wonderfully complex genes that also control how they develop from a single fertilized egg into an adult fly. These are called homeobox or “Hox” genes and it turns out their analogues are conserved throughout the animal kingdom. In this nice review of their functions, the following picture shows how the gene family controls development in the anterior – posterior development of the fly AND the mouse embryo.

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Screen Shot 2018-12-15 at 3.39.27 PMWhen things go wrong in the fruit fly (Drosophila), you can get a fascinating mutation that makes the fly look like this, with legs appearing where there should be antennae. In humans, analogous mutations can result in having extra fingers or malformations. You can read in more depth about how the Hox (a subset of the master homeotic regulator) genes are regulated at the Kahn academy in this article.

OK, you say, but what could this possibly have to do with prostate cancer? Ah, that’s what I find fascinating. Cancer is a superb example of dysregulation of the genetic programs that make cells behave. By the time you get to an animal developing a prostate gland, there are countless regulatory genes that must each turn on or off at the right time in embryogenesis. And just as “ontogeny recapitulates phylogeny“, oncology recapitulates ontogeny. One of these homeobox genes, HOXB13 was discovered to be mutated in studies of families with hereditary risk for prostate cancer by Johns Hopkins investigators several years ago. This gene interacts with the androgen receptor, so it makes some sense that the prostate gland would be affected by mutations. Further studies of families with this mutation indicate that if you inherit one copy of the G48E mutation, your risk of developing prostate cancer is 2.6 fold increased.

Whereas testing for such genetic mutations (and many others) used to be the provenance  of research labs, we are entering a time in medicine when genetic testing is becoming “mandatory” for best practice care. The following criteria are now used to help discern who might benefit from such testing:

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This table comes from a company, Myriad, that is now advertising for its own cancer risk gene panel, but there are several such companies and panels of genes. Although we (I) still don’t send off a genetic panel test to Myriad, Foundation Medicine, Invitae or the other companies in all patients, we are rapidly approaching the time when that will be standard. The challenges (as outlined in this article) are which genes should be tested, and what to do with the results. Some mutations such as those involving DNA damage repair, are already recognized as useful in directing therapy. For now, it is a topic best discussed with a genetics counsellor, and I fear, even more importantly one with an interest in prostate cancer if you can find one. Most of us physicians are struggling to keep up with which panel (if any) to order and when to order it.

So just remember when you see that little fly emerge from your fruit box this season, he/she/it has made immeasurable contributions to cancer research, and be thankful for all the science that is helping us to understand our amazing world.



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Filed under General Prostate Cancer Issues, Prostate cancer therapy, Targeted treatment

The Hits Just Keep on Coming

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I have a hiking companion who loves math, computers, and to a large extent, eugenics. He posits that we will eventually understand the human genome so well that we will be able to make all humans “smart” or “better” through genetic engineering. I argue back endlessly, with little success, that his definition of “smart” and “better” may not be shared  by everyone (he counters that these definitions will be left to the parents…) and that there will be unintended consequences of diving into our DNA with CRISPR/Cas9 technology.

The wonderful complexity of humankind is, of course, reflected in every single cell in our bodies and in all of our cancer cells as well. The debate over the number of synapses (or permutations) in our brains versus atoms (or stars etc.) in the observable universe is well beyond my comprehension. Unfortunately the “much simpler” question of how many things go wrong in cancer cells is also mind boggling. Hence, the phenomenal work of one of the West Coast Dream Team’s recent publications is not surprising. A reductionist view is shown in this diagram from their paper published last month:

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The scientific team, using funds from PCF, SU2C, and Movember (among others), did a whole genome analysis of metastatic tumor specimens from 101 men with castration resistant (hormone insensitive) prostate cancer. There is an excellent report on this work from the UCSF News Center here. Lest you believe that the results have resulted in an “aha moment” that will lead to “A prostate cancer cure”, you might do as I had to do and Google the word I had not heard of in the above figure, “chromothripsis“. Rather, the research leads to some very important insights that will doubtless contribute towards more effective therapy for 1000’s of patients eventually. By looking at the structural variants in the DNA that occurs outside of expressed genes, a much more complex picture of what drives castration resistant prostate cancer (CRPC) becomes evident. For example the androgen receptor (AR) is over-expressed in the majority of metastases and this study found a region of the “junk DNA” (non-coding for genes) that lies 66.94 million base pairs upstream of the AR that was amplified in 81% of the cases. This was 11% more common than the amplification of AR itself – an indication of how important the DNA controlling a gene like AR is, compared to the gene itself. So much for calling the DNA that doesn’t code for a protein “junk”!

A second example is the insight into patients who have alterations in a gene called CDK12 that may render them more sensitive to one of the “hottest” areas of cancer research, the use of checkpoint inhibitors of the PD-1 pathway I described in my last post.  This abnormality results in the cancer cells having an increased number of “neoantigens” (targets) for the immune system to attack as shown in this illustration from another recent exceptional paper.

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The ongoing research from the many scientific teams focused on prostate cancer is awe-inspiring when you consider the complexities involved in the two figures in this post alone. Even getting a complete picture from a single patient is impossible, given the genetic instability and the variable mutations found in different metastases. Remember, this team looked at the DNA from only one (or a few) of the many metastatic sites found in each patient. Other studies have shown lots of different mutations depending on which site is evaluated as I reviewed here.  In spite of all of this complexity, the ability to at least begin to understand what is going on “underneath the hood” is the way forward, and just as we can recognize Fords vs Chevys vs Toyotas, “brands” that emerge from such studies will lead to treatments that are more appropriate for certain classes of patients. As we have known for a very long time, the most common feature is the “gasoline” of testosterone, and how it fuels the amplified AR has remained an effective target for the newer drugs like abiraterone, enzalutamide, and apalutamide. Perhaps studies such as this one will lead to a way of kinking the hose upstream of the gasoline nozzle, or throwing sand (immunotherapy) into the engine itself. But… to admit that we will never understand it all (or design the “perfect human”) still seems an appropriate expression of humility to me.


Filed under General Prostate Cancer Issues

Improving our focus

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I have had two life changing experiences in focusing. The first was when my wife discovered the Myers-Briggs personality classification system and found I am a “strong P”. This meant I couldn’t help it when I was on my way to take out the garbage, noticed a light had burned out, put the garbage down and went to get a light bulb, but found that there was a spot on the carpet that needed cleaning and finally found the carpet cleaner but an hour later wondered why there was a garbage sack in the hall. Prior to her discovery, she just thought I was an idiot, but she became [somewhat] more tolerant of the foibles when she could “classify” me. The second was when I had my congenital cataracts removed and new lenses inserted in my eyes. It was a whole new world of color. I had been living in a fish tank with scum on the glass and “wow, the world is really pretty!” was my response when I took the patches off the next morning. “Trees have LEAVES!”

Focus in understanding prostate cancer is becoming clearer as well. For several decades we have known that the Gleason scoring system is pretty darn good at predicting the cancer’s behavior, adding a lot to what we knew when there was only the digital rectal exam… “Oh, oh, that feels like a really big tumor” or “Maybe I’m feeling something but I can’t be sure”.  Then came the number of biopsies positive, the percentage of each core, differentiating 3+4 vs 4+3, and now an avalanche of new molecular markers, briefly reviewed here. Combining the old standby risk categories with the newer methodologies has been challenging.

A recent paper in the JCO provides us with one way of integrating the old risk categories with the newer molecular classifications. Using the widely adopted risk categories of the NCCN, the authors added to this, one of the more mature molecular classifiers, the 22 gene Decipher™ scoring system to reclassify (focus) a new model to predict outcomes. As I explained previously, these genetic tests are typically developed looking at the level of gene expression in biopsies or in removed prostates in a group of patients for whom an outcome is known (examples include prostate cancer free survival at 10 years or freedom from metastases at 5 years). The investigators (or companies) then go to a different institution or collection of biopsy material and see if their gene expression model developed from the first group accurately predicts the outcome in the second group. This is called “validation” of the test. Decipher has done all of this. The question is how it might change the risk classification of the “old” system.

This figure illustrates how it plays out when a large number of institutions collaborate to study the information gained and develop a new model.Screen Shot 2018-04-28 at 10.16.05 AM

As an example of how this can be used in the “real life” clinic, we are often faced with a patient who has a “favorable intermediate” prostate cancer. Let’s say this is a 75 year old man with excellent health. Should we advise that he adopt a “watchful waiting” strategy, given his age and the relatively low risk? By adding the genomic test, you can see that 27% of the time, this might be a bad recommendation. Similarly, in the unfavorable intermediate group, 40% of patients are moved into a high risk category. Such a patient might be well advised to “do more” (example: more prolonged ADT with radiation, or use of brachytherapy in addition to external beam radiation if they had chosen radiation therapy as their preferred treatment modality).

These kinds of improved focus will allow investigators to do better studies prospectively as well. In breast cancer it is already a standard of care to do molecular classification of certain stages and types of tumors, allowing women to make far better decisions on whether (for example) to take chemotherapy in addition to surgery/radiation. In prostate cancer, where I have been concerned that we aren’t “racing for the cure“, rather we are “crawling for the cure”, it looks like we may be catching up. Research is the answer – sign up and contribute!

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Filed under General Prostate Cancer Issues, Prostate cancer therapy

3 Articles and a forth

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OK, I admit to a sleazy, seemingly misspelled word to attract attention. At least I didn’t tweet it at 3AM. So what about the “forth”? I’m using it to remind you to sally forth in your search for information about prostate cancer. I previously wrote a blog giving some practical instructions on how to find the latest research publications on prostate cancer that you can find here. Another possibility, if you want to be overwhelmed is to subscribe to the Prostate Cancer Daily, published by Uro Today. So far as I can tell it is open to all, presents the original abstracts, and links via PubMed to the article itself. I now realize that the prediction of patients knowing more than their doctors about a given condition is glaringly obvious, something I discussed when I first wrote about the Internet and Oncology two decades ago.

So, on to the 3 articles: Typically, the most important articles in medicine are published in high profile journals. The premier one for medical oncology is the Journal of Clinical Oncology, JCO. The editors recently published a “best of genitourinary cancer, 2017” edition in coordination with what we medical oncologists call “GU ASCO” (actually co-sponsored by ASCO, ASTRO, and SUO). I thought it would be of interest to briefly re-cap the 3 prostate articles chosen for that edition.

ARTICLE 1: Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. This study compared the more potent anti-androgen, enzalutamide (Xtandi™) to the older drug, bicalutamide (Casodex™) in patients who had become resistant to initial hormonal therapy. About 2/3 of the men had positive scans, while in 1/3 the resistance was detected only by a rising PSA without a positive scan. As we might have expected from the way enzalutamide was developed, it was clearly superior, with progression free survival of 19 months for enzalutamide vs. 6 months for bicalutamide. In an ideal world, we would use enzalutamide instead of bicalutamide in almost all cases where an antiandrogen is indicated. However, the increased cost of this drug is dramatic, and there may be other options or confounding issues with interpretation of the study.

ARTICLE 2: Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer. This article reports on one of many studies looking at whether radiation therapy treatment times can be safely shortened by increasing the dose of radiation given with each treatment and giving fewer treatments (fractions). The underlying principles are that tumor cells cannot repair DNA damage from radiation as quickly as normal cells, so giving radiation in small fractions daily allows killing of the tumor while normal cells repair most of the damage. Giving all of the radiation at once would kill every cell (and the patient).  Experimentally, prostate cancer cells may be more susceptible to larger fractions, and this study demonstrated that a radiation therapy course could be safely shortened from 41 sessions to 28 sessions with similar “cure” rates at 5.8 years of followup. This is a general trend in radiation therapy for prostate cancer. Using newer radiation focusing technologies (IMRT, IGRT, Stereotactic radiosurgery, etc.) it is possible to treat prostate cancer with as few as 5 treatments, although the long term efficacy is still unknown, and the addition of androgen deprivation to radiation treatment at any dose also improves efficacy. How to combine these approaches, the optimal duration of ADT, and which patients should stay with the older methods is still uncertain.

ARTICLE 3: Improved Survival With Prostate Radiation in Addition to Androgen Deprivation Therapy for Men With Newly Diagnosed Metastatic Prostate Cancer. Proudly, many of the authors on this article are from the University of Colorado Cancer Center. The authors used the National Cancer Database to determine whether patients with metastatic prostate cancer, traditionally treated with hormone therapy (ADT) only (although more recently with hormone therapy plus chemotherapy) benefit from also radiatiScreen Shot 2015-10-30 at 11.02.16 AMng the prostate itself. The analogy would be burning down the barn after the horse has left (with apologies to my radiation therapy colleagues who never like to compare radiation
treatments to burning). The patients who had their prostates radiated
had a 5 year survival of 49% compared to 33% for those receiving ADT alone. Removing the prostate surgically also worked. The prostate may also be a site where metastatic cells from another location return, as illustrated in this picture and discussed here. The take home message is that the cancerous prostate may continue to “seed” cancer cells to the rest of the body, or be a home for circulating tumor cells and getting rid of it, even though not curative, may be a good idea (toxicities and costs aside).

Consider yourselves updated! (sort of…)



Filed under General Prostate Cancer Issues, Prostate cancer therapy, Uncategorized