Today is the two month anniversary of my surgery, and I am happy to say that everything has gone well so far. It’s hard to believe it has been that long already. The challenge moving forward will be keeping an even keel in the face of prolonged, ceaseless uncertainty about the risk of recurrence.
“Time goes by so slowly / and time can do so much…”
The good news is that time is on my side: I may dabble in visualization, nutraceuticals, and traditional Chinese medicine, but at my core, I’m a full-blooded supporter of modern molecular medicine. In that spirit, I’ve compiled a list of seven predictions about what the next ten years will bring to the treatment and management of glioma. Although I hedged a little bit in the title by putting the modifier “Hopeful” in front of “predictions”, every one of these predictions is based on research that’s on-going and maturing as we speak. I don’t think I’m stepping out on a limb on any of these.
1. Molecular contrast enhancement for MRI detection of very small low-grade glioma
Primary brain tumors are very rare in the grand scheme of things at only 6 incidences per 100,000. Nevertheless, some physicians estimate that the “at-risk” population for glioma is much larger. An MRI-based study of otherwise healthy volunteers at NIH showed that 3 of 1,000 had an asymptomatic glioma. That’s several orders of magnitude more common than we would predict based on population-level incidences, and it indicates that many glioma happily never progress and / or are cleared by the immune system in due course. Improved screening of these “at-risk” individuals, however, may dramatically improve outcomes by allowing tumors to be detected early when they’re more readily treated with surgery, and before they have the opportunity to transform and / or cause catastrophic neurological damage. Improved MRI-detection can also guide surgeons’ hands to improve the quality of resections and eradicate every last tendril of problematic cells.
Some investigators have noted that folic acid is specifically taken up by glioma cells, and efforts are being made to use this to improve contrast and resolution of MRI-based detection. Much chemical engineering and clinical optimization remains to be done, but this is a very attractive approach to improve the quality of glioma management and detection. I think it’s reasonable to predict that a generation from now, people will be horrified to learn that we waited until people had a seizure to figure out if they had a brain tumor or not.
2. Next-generation sequencing diagnostics for glioma from whole blood
Although some physicians recommend regular MRIs to screen the population for brain tumors, the problem is that MRIs aren’t cheap (I know because I read the medical bills that keep filtering in), and the radiologists’ time isn’t cheap. MRIs will likely never become a routine, population-level screen for early brain tumor detection. On the other hand, next-generation sequencing keeps getting cheaper and cheaper, and the analytical protocols are getting better and better, and the computational challenges can be met with cloud-based hardware (hat tip to my friend, Kyle). For these reasons, there’s a great deal of enthusiasm for generating blood-based “sequencing MRIs” to diagnosis and genotype tumors as early as possible. It’s tempting to predict that in a generation’s time, our routine blood-work from primary care physicians will include a sequencing-based screen for every possible flavor of cancer.
3. A molecular genetic understanding of the natural history of glioma
Several recent papers have used next-generation sequencing to genotype hundreds of different primary brain tumors. We’ve learned some useful things from these papers. It’s been known for a while that most low-grade glioma possess mutations in either IDH1 or IDH2 while most GBM are IDH wild-type; IDH mutants thus being considered to be advantageous for patient survival. These new papers have discovered a third cluster of low grade glioma tumor genetics: IDH mutant, with no co-deletion of 1p/19q, and a frameshift mutation in ATRX with a TP53 mutation. These tumors (of which mine was a member) have an intermediate risk profile and are now the subject of intense investigation. It’s comforting to know that people in the field recognize your specific tumor as a priority for investigation.
Related to this, and consistent with points 1 and 2 above, we really know very little about how glioma start, and how they progress over their long, clinically silent phase. By combining better imaging tools with effective molecular genetics, we can learn a great deal about the normal course of a glioma’s life history, and thereby identify the critical periods and weapons that would be the most effective for intervention.
4. Specific targeting of therapeutic agents to glioma
Point #1 above describes an approach using folic acid to improve contrast and resolution of diagnostic MRIs. The same basic principle can be used to deliver drugs to eradicate tumor cells. Likewise, polio virus specifically infects glial cells and has been engineered to kill GBM. In both cases, sophisticated biochemical engineering can convert anti-tumor strategies from carpet-bombing to smart bombs.
5. Non-invasive suppression of tumor growth
Novocure has developed a cap that can be worn on the head which generates strong electromagnetic fields which repress cell division in the brain. As of right now, it’s only approved to treat recurrent GBM, although there’s no reason to think that the general principle doesn’t apply to low-grade glioma as well. As an added bonus, my oncologist Dr. Ansstas is heading the clinical trials at WashU. Non-invasive is always my favorite option, especially since I had an outrageously invasive intervention two short months ago.
6. Tumor vaccines against IDH1 mutants
A team of European and American scientists have immunized mice against the mutant antigen found in most patients with IDH-mutant glioma. They found a striking reduction in tumor volume and growth in as little as two weeks. Clinical trials in humans are on-going. Similar tumor vaccine trials for GBM and other brain tumors are on-going using dendritic cells and other approaches.
7. Specific inhibition of mutant IDH1 activity
Because IDH1 mutation is the initiating and causal genetic lesion underlying glioma genome instability and tumor growth, a number of pharmaceutical companies have begun engineering small-molecule inhibitors of its activity. Several of these show great promise in pre-clinical studies and have moved on to early clinical studies. Perhaps these drugs won’t be quite as world changing as Gleevec was, but the basic principle is the same. In any case, “Just Win, Baby.”
A generation ago, polio was a terror that was eradicated with smart, timely use of biomedical research. Within my lifetime, HIV/AIDS was an absolute nightmare. Today, it’s manageable with the right protease inhibitor cocktails, and patients can live normal lives if they take care of themselves and follow their regimen correctly. Likewise, many cancers have been converted from awful to manageable within the last ten years. Brain tumors are currently a nightmare, but there’s many reasons for optimism about the prospects in the next ten years. Stealing from the Righteous Brothers again, I say “Godspeed.”
I imagine that many years from now, when I explain what it was like to have a brain tumor in the early 21st century, people will be horrified that I had to wait to have a seizure to detect the risk. It makes me shudder to think of all the bad times and places I could have had that seizure instead of in my bed, next to a physician. Also, I’ll have to explain to a skeptical audience that having a sizable chunk of my brain removed was not only sensible but almost certainly saved my life.