Practice Update: Oncology

Q & A 32

Emerging Science in Gliomas and Glioblastomas: A Review Interview with Wolfgang Wick MD by Jennifer N. Caudle DO

Dr. Wick is Division Head of Neuro-Oncology at the German Cancer Research Center (DKFZ), Program Chair of Neuro-Oncology at the National Center for Tumor Diseases (NCT), and Professor of Neurology and Chairman at the Neurology Clinic in Heidelberg, Germany.

Dr. Caudle: Currently, molecular subtyping serves primarily a predictive, prognostic purpose in gliomas. One study presented here actually revealed that targetable fusions were found via RNA sequencing and up to 10% of astrocytomas. Another study demonstrated clinical activity of vemurafenib in BRAF mutant gliomas. So do you foresee targeted therapies playing a role, an important role rather in managing gliomas in the future? And if so, which other genes or mutations do you predict will be the most attractive or useful candidates? Dr. Wick: Yeah. I think it’s important, very important topic. So we have to look at gli- omas as a bunch of disease. It’s not just one disease. There are gliomas, and the BRAF-mutated xanthoastrocytoma is a very nice example, that are driven primarily by a single lesion or at least in a single path- way. Pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and probably also a few others are really dependent on the BRAF and MEC pathway. And therefore, in that disease, these inhibitors will be effec- tive. We don’t know how fast resistance is evolving, but they will be effective and we’ve seen that. So patients are not only stabilized over a prolonged period of time, but the tumor tissues actually responding to the treatment. So cells are dying, cells are going away with that treatment. So this is important. Dr. Caudle: Yes. Dr. Wick: Second, if you are looking at the

I think fusions are an overlooked molecular entity in gliomas. So it’s a very attractive target. We understand that those fusions need to be assessed with the genetics that we are doing. We were focusing on the axon. We are doing that. We will miss the fusion, so RNA sequencing is something we should look for.

broader scope of gliomas, this is a very heterogeneous disease. So what we need to define is what are really the driv- ing alterations in that disease. We look at IDH mutations, so the mutated isocitrate dehydrogenase where several compa- nies are now building inhibitors. There will be glioma patients benefiting from that approach. I think this is for sure. There are a lot of patients harboring a TERT mutation, a certain telomerase activating alteration, which is also something which is very high up in the hierarchy of the alterations in the tumor tissue and therefore may be an attractive target. There are other alterations like all the EGF receptor alterations, which play a big role in lung disease, other cancers. They are only in the minority of tumor cell subclones and therefore probably only 20% to 25% of cells in a given patient are responding and this is not perfect alterations. Coming to that abstract, I think fusions are an over- looked molecular entity in gliomas. So it’s a very attractive target. We understand that those fusions need to be assessed with

the genetics that we are doing. We were focusing on the axon. We are doing that. We will miss the fusion, so RNA sequencing is something we should look for. There are certain panels, also DNA panels that are already integrating the fusions and several of those fusions are and will be assessable for treatments in the future. I’m pretty confi- dent that we will have more drugs targeting those fusions and then get some benefit, at least in selected patients from it. Dr. Caudle: Right. Right. That makes sense. And you know, sort of, I think we mentioned a little bit about hopes for the future, you know, let’s talk about maybe the past year. What do you feel is the most significant advance in managing CNS malignan- cies over the past year and what do you see as some of the most promising treat- ments or therapeutics that are currently in development? Dr. Wick: So let’s start probably with a very conceptual point. Dr. Caudle: Okay. Dr. Wick: I think we are now on this turning point of really better understanding the

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