Metabolic Pathways May Lead Researchers to Novel Therapeutic Targets in Neuro-Oncology

Shannon Connelly
Published Online: Monday, Dec 26, 2016

Howard Fine, MD

Howard Fine, MD

In neuro-oncology, newfound interest has sparked investigations into metabolic pathways in tumors with the hope of identifying novel therapeutic targets.

According to Howard Fine, MD, researchers often get excited about these new, “hot” discoveries, but then lose track of them for several years, only to rediscover them later on down the road.

“With new knowledge, all of a sudden there’s a whole new level of science brought to it,” said Fine, director, Brain Tumor Center, Sandra and Edward Meyer Cancer Center, and chief, Division of Neuro-Oncology, Weill Cornell Medicine. “I think that’s where we are with tumor metabolism.”

In an interview with OncLive, Fine discusses the reasons behind this renewed interested in metabolic targets, the impact it has had on the treatment of patients with gliomas, and what he sees for the future of neuro-oncology in this area.

OncLive: Why has there been renewed interest in metabolic targets?

Fine: Metabolism in cancer is actually an interesting story in that some of the earliest approaches we used to try to fight cancer, starting 30 to 40 years ago, tried to target the metabolic pathways, and some of our earliest drugs, like methotrexate (Trexall), to target cancer interfered with folate metabolism and that was really our major way of fighting cancer.

With the advent of molecular biology and genetics, metabolism and the idea of targeting the aberrant metabolism tumor kind of became passé, kind of like pharmacology did. We got in to the genetic age and people began to forget about it, until we began to realize that many of the oncogenic pathways and many of the deregulated signal transduction pathways that we’ve been studying actually end up converging on pathways of metabolism.

There’s been an increased interest in all [areas] of cancer, and certainly neuro-oncology, to not only begin to really understand the aberrant metabolism in tumors to better understand tumor biology, but also to realize that there may be great opportunities for novel therapeutic targeting.

This particularly came to light with the discovery, 5, 6, or 7 years ago, of the IDH mutation found in a large percentage of low-grade gliomas. The IDH mutation is in a gene that is central in the tricarboxylic acid (TCA) pathway and is a basic metabolic enzyme. That again brought to light how intrinsically important metabolism is in tumor biology, glioma biology, and the potential therapeutic options thereof.

What was the significance of this finding?

I think that brought a lot to light. In fact, it’s the first mutation that has been shown in a TCA enzyme that produces a unique metabolite that’s now called an oncometabolite. It’s kind of the paradigm for how metabolism is important for any cancer, so it has a special place in the heart of neuro-oncologists.

I think that increasingly so, in all of oncology, people are beginning to pay a lot more attention to the importance of cancer metabolism and how it may offer new therapeutic opportunities.

What do you think is on the horizon, and what are you hoping to see?

I think IDH1 is just the tip of the iceberg, although I don’t know that we’re going to find that many new mutations in oncometabolites. It is quite clear, and we’ve know this for many, many years, but now we’re beginning to really understand the molecular details of it, that the metabolism in tumors is quite dramatically different than it is in normal tissue.

When you think about therapies, what are we trying to do? We’re trying to find ways in which tumor tissue is different and behaves different and has a different biology than normal tissue because that gives a therapeutic target. If you can find the therapeutic ratio that’s different between normal tissue versus tumor tissue, that gives you something to aim at therapeutically without worrying about overlapping normal tissue toxicity. Metabolism is just that—it’s a very complex series of biochemical pathways that appear to be, in many respects, quite different in tumor tissue than in normal tissue; so it offers, theoretically, a very promising new area to therapeutically target.




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