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GBM science from a scientist living with GBM: Patrick K-Mc

About me
I have a BS in biochemistry with an emphasis on the genetics of neurodegenerative disease, I have an MS in biomedical science; I’ve flunked out of medical school; and I’ve had three different brain tumors since 2002. My GBM story.

I’m not a qualified scientist, researcher, or physician; and I tend to be facetious and flippant, I like to use analogies, and I am more than a little eccentric, but, hey, I’ve survived three more brain tumors than the average person, which means I’ve got something figured out.

The first thing to keep in mind is that scientific knowledge has a half-life. 1000 years ago, we all knew the Earth was the center of the universe; 500 years ago, we all knew the plague was a punishment from G-d, and 30 years ago, I knew Santa Claus was real. In the first week of medical school, we’re told that half of everything we’re taught will be wrong, outdated, obsolete, or irrelevant before we graduate; so, what I tell you today may very well already be inaccurate. Take everything I’m about to tell you with a grain of salt, please fact check me; if I’m wrong, let me know in a nice way.

Cancer Biology
First topic, let’s talk cancer biology, and we have to discuss some cellular biology, immunology, and genetics along the way. I’m gonna try and make this painless.

Far and away the most-frequently-asked question I see is, “Why did I get cancer?” The simple answer is that cancer is the default cellular setting. Most of us are descended from single-celled life – that’s bacteria, like the Bubonic Plague, E. Coli, and Tuberculosis; and protists (we’re a little closer to them) like amoebas and malaria. In those cases, if you are the biggest, fastest-dividing, fastest-growing cell in the system, you’re winning, from an evolutionary standpoint. It’s the cellular equivalent of Mad Max – if you’re the last radioactive cannibal in your timezone, all those abandoned supermarkets, muscle cars, and elk are yours for the taking. Bacteria (and some protists, possibly) are immortal, can divide forever, and can grow as large as their nutrients and certain laws of physics allow.

In multicellular life (or, in the Mad Max analogy, if Tina Turner buys a house in a subdivision in Pasadena), things get a little more complicated. If you’re the biggest, fastest-growing, fastest-dividing cardiac muscle cell, you’ll steal resources from your neighbors, kill the body, and eventually die. In our Mad Max analogy, it’s like Tina Turner getting a condo in Pasadena, and trying to maintain her cannibalistic, Thunderdome lifestyle – she’s eventually going to destroy all the supermarkets, kill all the neighbors, and be left to fend for herself.

Multicellular life has some ways to stop those highly-individualized cells from going rogue. First, there’s the Hayflick Limit – each cell in your body can only divide a certain number of times before it dies. There’s anchorage-dependence, where cells need to be in contact with other cells in order to divide and get nutrients – they die if they’re not attached to other cells.

To mix metaphors on the Mad Max one; whereas single-celled life plays by extremely individualized, post-apocalyptic wasteland rules, the cells that make up your body are like a symphony. They play by very specific, coordinated rules to perform a complex pieced of music, which means growing, making proteins (or performing other cellular functions), dividing a limited number of times, and then dying.

And, yeah, the downside of all that is that the Mozart concierto that is your life eventually ends; the goal of multicellular life is like the goal of any artist – to inspire others (in this case, pass on your genes, rear those genetic carriers, and then make room for them). In this analogy, your genetic code is like the sheet music that everyone follows, and your immune system is like the conductor – they scowl at the timpani when it gets too loud or goes too fast.

To coordinate cellular activity so that you don’t get a rogue group of trumpets, guitarists, and trombones forming a mariachi band on the opening night of Nutcracker (or lymphoma in reality), your genetic code has two types of genes involved – proto-onco genes, which cause cells to grow and divide; and tumor-suppressor genes, which deactivate the proto-onco genes.

When you have a tumor suppressor gene permanently deactivated and a protooncogene activated, to quote you my immunology professor, “You have cancer.”

That’s it. Just two mutations in a single cell, and your body is no longer a symphony, it’s post-apocalypse Australia. There’s a simple solution to that one, right? Just avoid carcinogens. Except you can’t. Sunlight and oxygen are carcinogenic; try and live without them.

And, in total honesty, your body is really, really good at detecting and repairing this damage – my long-suffering immunology prof once said he calculated that every cell in your body gets over 10,000 genetic “challenges” each day, but only two or three dozen permanent mutations in your entire body per year. To further paraphrase my professor, there is no such thing as a risk-free life; you just have weigh which risks and how much risk is acceptable. That’s an important concept in cancer treatment, because a lot of the long-term side effects of radiation and chemo are more (or different, anyway) cancers.

Once that single cell is cancerous, it can remain dormant and undetected by your immune system (which recognizes and eliminates rogue cells or completely identical cells very efficiently) while “recruiting” – passing those mutations on to – other cells, although we’re not sure how that process works. When you get enough cells together, you have a tumor (or a non-solid tumor in the case of blood cancers), and that’s when it’s usually detected.

Brain Tumors
It’s at this point where we need to differentiate brain tumors from other forms of cancer, and why treating it is such a challenge. Your central nervous system – brain and spinal cord – are a completely separate, biochemically and anatomically-walled-off system, and it’s immunologically privileged – meaning there aren’t very many immune cells operating there.

Astrocytes – the cellular forerunner to GBM – function as the brain’s immune system, although there are a few dendrocytes and T-cells in your central nervous system. That biochemical barrier that keeps you from keeling over after a single shot of tequila is called the Blood Brain Barrier (I’ve seen that as B3, which I prefer – it’s a biochemical phenomenon, not a vitamin), and it keeps chemo from getting to the brain and wiping out GBM.

It also keeps GBM from getting out of the central nervous system and getting to your liver or bones. Which is a double-edged sword – your tumor isn’t likely to escape outside of your skull and spinal column (there are a few documented cases of that, but, if you think brain cancer is rare, brain cancer that gets elsewhere is like escaping Alcatraz), BUT, I feel that if tumor patients heard words like “brain cancer in-situ” instead of “benign brain tumor,” we’d probably react more quickly.

GBM that’s metastasized from other places (usually prostate cancer or lung cancer) (side note; the only guy I’ve met who’s had more neurosurgeries than me is a chronic prostate cancer patient), is called “secondary GBM;” if it originates from the brain, it’s “primary GBM.” “Primary” GBM tends to be more resistant to treatment, more-aggressive, all of the horrifying stuff you’ve heard about this disease.

I have “secondary” GBM – almost-certainly derived from my grade 2 astrocytoma. Usually, primary GBM is far worse than secondary GBM, but I’m using words like “usually” and other strategic, weasel words, because this is a poorly-documented, rare disease that seems to be inherently unpredictable.

Which is why OBB is so critical – it’ll get data on this disease and how it “behaves.” Other terms like MGMT methylation (which is good), or IDH mutations, are just predictors of how well the tumor will respond to conventional treatment, but I’d caution everyone about predictions surrounding an unpredictable disease.

GBM Treatment
Killing cancer cells is remarkably easy. If we didn’t care about patients surviving, we could cure every single disease known to science, and every single disease imaginable – just a quick bath in Agent Orange, and no more cancer! No more patient, either, but that’s where things get tricky.

Individualized Treatment
Personalized medicine is just physicians adapting their treatment and approach to you in a way that’s as aggressive and effective as possible, while keeping you alive and maintaining what you’d consider an acceptable quality of life.

My first tumor, the neurocytoma I got at age 17 (for which I was asymptomatic), was treated with neurosurgery, which was like sand-blasting a soup-cracker – it put my right cerebral hemisphere at three standard deviations below normal for electrical activity (electrical activity in the brain is correlated with neuronal activity, so, in English, I was far dumber than I was used to).

An individualized approach to that would have been for all my physicians to get in a room with me, discuss what they’d noticed, what the treatment options were, and the associated risks and benefits of each. Instead, the medical staff involved scared the hell out of my mother and me, and pre-emptively gave me a nine-hour surgery without discussing things like gamma knife surgery or experimental options. Getting a second opinion in that case probably would’ve been beneficial, and lead to more possible treatment options (probably leading to one that would’ve been less disruptive to my life).

Individualized medicine is, essentially, tailoring treatment to maximize benefits while minimizing risks and costs, and it will probably come in a variety of different treatment modalities, from lifestyle modification (diet, exercise, psychiatric support, social support, etc.), surgery, chemo, and, possibly, immunotherapy.

A few quick words on immunotherapy – remember that bit about cancer evading the immune system? – immunotherapy is, essentially, retraining your immune system to recognize those cancer cells and go after them, and it can come in a variety of different forms.

Jessica Morris of OurBrainBank is getting a modified herpesvirus that’s supposed to cause an immune reaction; I was enrolled in a trial for a very exotic form of immunotherapy that would extract and genetically “reprogram” my white blood cells to recognize tumor cells (before it unexpectedly jumped a few grades and disqualified me from that treatment) (remember, this is an unpredictable, poorly-studied disease).

Personalized Medicine for GBM
Personalized medicine is really important with GBM because this isn’t some sort of monolithic disease, but dozens – possibly hundreds – of different, distinct subtypes of brain cancer that have only a common progenitor cell.

To get a personalized approach to GBM, you will have to get your tumor biopsied. Which is also usually the first step in Standard of Care – SOC – neurosurgery. As Al Musella noted (and I can attest), surgery is rarely a good long-term single solution, but it does offer a great starting point for other treatments that could, potentially, be more beneficial than the one-size-fits-all SOC (which seems to have become an excuse for, “We’ve done all we can; insha’allah” for both survivors and physicians).

Standard of Care
SOC for GBM right now is: neurosurgery, 4-6 weeks recuperation, 6-ish weeks of chemoradiation, and 12 cycles of Temodar. The Optune Device is rapidly gaining favor and has been added to the SOC in some places.

Is the SOC is the best option for every patient? Given the disastrously high mortality rate of this disease, I’m skeptical. Having said that, I’d also say that science absolutely does not have enough data to make a solid judgment either way. I don’t know how many of us complete SOC; but right now, I’ve only heard of a half-dozen of us, maybe, who have completed SOC.

The number of GBM patients I’ve met or heard of who discontinued SOC or had near-fatal reactions and had to be pulled off of SOC is easily 3-4 times that. Some folks, like Cheryl Broyles, tolerate SOC remarkably well, and just keep going in for it over and over until they’ve racked up 20 years.

There’s a major issue when we talk about cancer like it’s a single disease – it’s just some rogue cells dividing and growing like crazy until they fatally encroach on their neighbors, and there are as many different cancers as there are cells in your body (because cancer cells are insanely genetically unstable, they mutate quite quickly, and, although this tumor might respond to chemo today; the next one might not) – which means there as many treatments, too.

What is the right treatment for me?
You want the right treatment, with the right tumor, and the right patient (if a patient vomits for three days after an infusion, it doesn’t matter if marizomib is a good drug; they’re going to discontinue treatment).

And, to that end, personalized chemo recommendations based on tumor biopsy results, will, I suspect, become the new second step in SOC.

I did a variation of SOC with an experimental, repurposed drug added to the chemo regimen (which I tolerated; that’s all I’ll say), which I think we’ll see more of in coming years. I think that GBM patients, right now, are like HIV patients in 1989 (the year before AZT was approved for human use on HIV infections) (AZT, ironically, originally failed testing as an anticancer agent in the 1960s); we really do just have to hang on a tiny bit longer.

Look at SOC as a starting place, and look at what else you can do to improve upon it or increase its efficiency. There is a direct correlation between how well patients tolerate initial chemoradiation and overall survival, so figuring out how to stay healthy and active during initial treatment is a good starting point. I’ve also written about medical marijuana – there is some initial research correlating it with making chemo more effective).

If the choice is between SOC or nothing; take SOC and quietly look into second opinions and other treatment options. (Even though SOC isn’t supposed to be as effective for unmethylated tumors; I’ve heard stories of people with unmethylated tumors just doubling down and getting through it).

Based on what I’ve seen and the data; a fatal factor for most of us is that we do go home when our oncologists use that terrible phrase, “We’ve done all we can” instead of hearing, “We’re at the end of our rope, seek help elsewhere.”