Tag Archives: science

Black holes and genetic laws


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I just finished reading Stephen Hawking’s last book, Brief Answers to the Big Questions, which I found more accessible than A Brief History of Time, written more than 30 years ago. Hawking’s abilities to explain the very (for me) abstract concepts of how no information can flow out of black holes and that the amount in there is somehow directly related to the cross sectional area of the hole was satisfying. As a very math challenged individual, I’m also a fan of Heisenberg and the perplexing issue that in the quantum/wave world of particle physics, you just can’t be certain about position and momentum. Yet, there are certain laws, like the speed of light, that are never violated, at least in the universe we live in.

So what does this have to do with genetics and prostate (or other) cancers? Here is a law: A always pairs with T, and C always pairs with G. In our biologic universe, without this law, no life as we know it could exist (prions may be an exception, but that gets too far into the definition of “life”). Yet, just as with the uncertainty of Heisenberg, the base pairing in DNA/RNA is not completely inviolable. Mistakes are made…and this can result in cancer. Cancer is a genetic disease and for anyone who hasn’t read it, I still recommend you avail yourself of the incredibly well written book, The Emperor of All Maladies. In the short time since that book was written, the explosion in our understanding of how genetic errors and cancer are related has been difficult to keep up with. The Cancer Genome Atlas (clever name, eh?) is but one example, and its use by scientists skilled in math (ugh) continues to help classify cancers based on how their mutations drive them rather than just how they look under the microscope or which organ they started in. Here is the math and the results one such analysis has on predicting survival for stomach cancer:

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As you can see, the prognosis and potentially the treatment for one subtype of “stomach cancer” might be very different for one patient than for another. Bringing this technology to prostate cancer, we already know the mutational landscape is vast. For example, this article looked at 1,013 different prostate cancers and found 97 significantly mutated genes, including 70 not previously recognized, and many present in <3% of cases. There is hidden good news in this story, in that the same mutational uncertainties that can give rise to cancer (breaking the law of AT-CG) also allows our immune systems to react to the novel mutated proteins that cancers now display. For an interview from this week’s NEJM on gene editing, click here.

Keeping up with this world of laws, broken laws, and “black holes” will be a remarkable challenge for patients and oncologists alike. My final recommendation for reading about this is a terrific article you can find here by George Sledge, one of the outstanding leaders in our field. He notes that even the most skilled oncologist, paired with the smartest of patients, will be unable to keep up. But remember this, you can’t go faster than the speed of light. That’s the law!

 

 

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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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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.

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Of Prostates and Teslas


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If you thought this might be an article about how your urologist shops for his/her newest fancy car, you are mistaken (sadly…). Nikola Tesla was a fascinating inventor and ultimately “mad scientist” at the turn of the last century. Every time you plug your cuisinart into the wall to chop something up, you are the beneficiary of his contributions to the alternating current coming to your kitchen and the motor driving the chopper. My favorite story (because of the local connection) was his laboratory in Colorado Springs, where he attempted to develop a method of transmitting power without wires. By creating YUUUGE electromagnetic fields, he could make lots of electrical things happen at considerable distances, including knocking out the power station for the city. Here’s a quote from the Wikipedia article:

He produced artificial lightning, with discharges consisting of millions of volts and up to 135 feet (41 m) long.[11] Thunder from the released energy was heard 15 miles (24 km) away in Cripple Creek, Colorado. People walking along the street observed sparks jumping between their feet and the ground. Sparks sprang from water line taps when touched. Light bulbs within 100 feet (30 m) of the lab glowed even when turned off. Horses in a livery stable bolted from their stalls after receiving shocks through their metal shoes. Butterflies were electrified, swirling in circles with blue halos of St. Elmo’s fire around their wings.[12]

Of course, for purposes of this blog, the key thing is that the strength of magnetic fields was named after him. When you get an MRI of your prostate, brain, or anything else, you are put into a machine with a superconducting magnet that produces 1.5 or 3 “T” of strength. At the risk of being completely wrong and oversimplifying, what happens in the MRI machine is that a strong magnetic field temporarily lines up the hydrogen atoms in the water that is 70% of “you”, and when these atoms “relax” they give off radio signals that can be converted to images. Details and images are here. Early on, my colleagues and I were fascinated by the possibility of using MR to investigate the prostate gland and published an article (completely ignored – cited only 3 times, so must not have been that important…) showing changes in MR that occurred after testosterone administration to castrated rats.

Now there are complex MRI protocols to image the prostate using techniques I don’t fully understand (multiparametric imaging) that give us remarkable pictures of the prostate gland. Here is one:

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Prostate gland with red arrow indicating a suspicious lesion that could be biopsied or followed closely.

As with any radiologic imaging technique, the skill of the radiologist as well as the equipment being used determine the accuracy of the MRI to diagnose a cancer.

While most of us learned how to “read X-rays” in medical school, it is beyond most clinicians to read MRI’s of the prostate. Fortunately, the radiologists have developed a system that helps us think about “how abnormal” some area of the gland is, called PI-RADS.  This can be very useful in thinking about what area to concentrate on when biopsying a patient, or in trying to determine whether surgery or radiation therapy should be altered if there is concern that the cancer is outside of the gland. An interesting question that is still controversial is whether the MRI could replace repetitive biopsies in a man who has chosen active surveillance. Particularly when combined with molecular techniques (see my previous blog here) to characterize biopsies, it may be that Tesla will be helping to do more than get you from one place to another or run your electric shaver. (Rock on, Elon Musk) To me, that is a pretty interesting outcome from knocking out all of the lights in Colorado Springs!

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