PracticeUpdate: Haematology & Oncology

FEATURE ARTICLE

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MicroRNAs in brain cancer treatment Interview with Steven Toms, MD, MPH, FAANS, FACS

Dr Toms, Chairman of the Department of Neuro Surgery at the Geisinger Health System in the US speaks with PracticeUpdate ’s Farzanna Haffizulla, MD, FACP, FAMWA of Davie, Florida, on microRNAs and their role in cancer metastasis and disease progression, and the development of targeted therapies for the treatment of glioblastoma.

of Massachusetts. They’re being looked at for a variety of different disease states right now, but we’re still a little far away yet from having therapeutics that are microRNA or especially epigenetically modified microRNA targets. Certainly, these may represent targets down the road, but as of right now, we don’t have those in our back pocket. Dr Haffizulla : Other than age and some of the other risk factors that are known for glioblas- toma, have we refined our approach as far as say a primary care physician in their office doing a proper assessment, a good history, a good physical? Looking back, what kinds of questions should be asked to see if a person is at risk, besides, of course, maybe ionising radiation exposure etc? Dr Toms : Well, exactly. Glioblastoma is a fairly rare cancer, as we know, about seven or eight thousand in the US in a given year. Typically, these don’t’ present with much warning. They can grow silently for years, or they can grow as transforming from a lower-grade glioma, or they can derive de novo in a matter of weeks or months, grow into a fairly large cancer. Most of the time their presentation is fairly insidious. It might just present with some headache or some non-localising symptoms, some slowly progressive neurologic signs such as speech disorders or inability to walk or move a limb. Sometimes they’ll present a little more suddenly, with a seizure or a stroke- like symptom. Typically, in the primary care physician’s office when someone comes in with a headache, a glioblastoma is not going to be first on the list. Dr Haffizulla : Sure. Common is common. Dr Toms : Exactly, and there are many, many more common things. So it’s very, very common that I, as the Monday morning quarterback, as it were, to the primary care physician (PCP), sees and can then put the story together that, “Ah ha, for the last few weeks there’s been something going on and perhaps it could have been found a little bit earlier.” Right now, though, with what we have in thera- peutics for glioblastoma, it’s not that critical for a PCP to find it a week or 2 weeks earlier.

The main thing to keep in mind for all the PCPs out there, is if you have headaches or localising neurological signs, to take them seri- ously, make sure that patient gets evaluated. Often these days they’re picked up through a very good PCP who sends them onto imaging, CAT scan or MRI, and that’s when they end up coming to see a guy like me. Dr Haffizulla : Of course. The hope is to have a prevention-based model so we can prevent these cancers from happening in the first place. Maybe refining our approach, again, some molecular therapies, and probably doing more personalised precision type medicine, we’ll probably be able to get there. Dr Toms : Absolutely, and now if we only knew what caused them. You know, certainly, people ask all the time, “What causes my glioblas- toma? Is it genetic?” Typically, we very rarely see them running in families, so it seems not to be typical genetic factors. Many people have been worried for years about exposure to their cell phones, high-tension lines, Diet Coke was a popular theory a while back, and if so, I’m in big trouble, but those haven’t seemed to play out. If I had to place my chip 50 years down the future on what we would know, I’d say it’s probably going to turn out to be viruses that we’re exposed too. They often end up integrat- ing into our genome, unbeknownst to us. If they integrate in the wrong place, they can turn on a gene that should be off, or turn off a critical gene, which then allows the cell to start growing out of control. There has been some early data in the last 5 years, showing that there are a number of viral genomes in a lot of the glioblastoma samples that we see and that’s an ongoing area of research.

it helps maintain the cellular signals that keep that cancer in a replicating or stem state in which it can divide, make other cancer cells, and help regulate the microenvironment. Obviously, these stem cells are the ones in the cancer that are most troublesome for us in clinical oncology. If we’re ever to eradicate a cancer, we have to kill off all of the cancer stem cells so that they don’t come back. We’re hoping that these new mechanisms that we’re finding of cancer stem cells maintaining their stemness, can then be exploited down the road, whether it’s through RNA interfer- ence, or ways we can change the methylation status of these and allow them to differentiate as a group into cancer stromal cells, which are more easily taken care of. We’re not sure yet, but we’re hoping this is going to be a brand new environment for us to regulate the way in which cancer cells are regulated and eventually treat it for us. Dr Haffizulla : Any microRNA targeted thera- pies in the works now? It might be a little premature to even think that we’re there, but sometimes these things happen concurrent to the scientific experiments that are ongoing. Any news to share? Toms : Not from our lab yet. Certainty, RNA interference and other things we’re working on, small non-coding RNAs, and working to sort of bind up or gum up RNA signals that are transcribed, have been pioneered by a number of places such as the group at the University

Dr Haffizulla: We’re going to talk a little bit about future thought processes, and maybe some sci- entific advances that may happen in the near future. Let’s focus on microRNAs and their role in cancer metastasis, disease progression etc, and targeted therapy development. Dr Toms : MicroRNAs, as you may know, are these tiny regulatory RNAs that weren’t even talked about 8 or 10 years ago. What we know about these microRNAs is that they combine genes, pseudogenes, and they help regulate the transcription of RNA themselves, which then turns into the proteins, which are the enactors or enablers of the things happening within the cell. What our laboratory has been focusing on is we’ve been looking at glioblastoma stem cells. We found an entirely new mechanism of microRNA regulation of proteins and RNA regulation. In the past, we’ve found that, again, there are these little binding sites that occur between pseudogenes and microRNAs that help regu- late. And we have found a new way in which the five prime end, or the upstream end of a microRNA can be methylated, which seems to then regulate several of the downstream genes that are known in glioblastoma and other cancers. When that five prime end is methyl- ated, it actually helps maintain the stemness of glioblastoma stem cells. So when we find these particular microRNA species are methylated at that five prime end,

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Watch the full interview with Dr Steven Toms on www.PracticeUpdate.com

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VOL. 1 • No. 4 • 2016