Expert Highlights Resistance to Targeted Therapies, Role of Epigenetic Changes in Melanoma

Helmut Schaider, MD

Dabrafenib (Mekinist) and trametinib (Tafinlar) have changed the treatment landscape for melanoma, both as single agents and in combination. However, resistance to these therapies is still a significant problem for many patients, says Helmut Schaider, MD, an associate professor at the University of Queensland in Brisbane, Australia.

At the 2016 Society for Melanoma Research (SMR) Congress, Schaider presented a study investigating resistance to dabrafenib and/or trametinib. The study identified chronic stress-induced multi-drug tolerant cells (IDTCs) and determined that prolonged activation of adenosine monophosphate-activated protein kinase (AMPK) using aspirin may delay the formation of these cells and prevent permanent drug resistance.

OncLive: Can you provide an overview of the study you presented at SMR?

What is currently being done to achieve that?

In an interview with OncLive, Schaider discusses why drug resistance may be due to epigenetic changes and not mutation-induced changes, as well as the role of immunotherapy/targeted therapy combinations in combating resistance.Schaider: I talked about the inference of metabolic proteins on epigenetics. We all know that now there are several options for targeted therapies, but unfortunately resistance is a problem for many of these patients, and then they relapse. We are interested in investigating potential targets that can combine with other agents to prevent this drug resistance.The combination of targeted therapy with immunotherapy is showing some promise for the future. There are so many combinations that may become available. But, still we need to think of things like side effects, toxicities, etcetera.

What more needs to be done and what is the end goal?

What is the mechanism of action in combining immunotherapy with targeted therapies to prevent resistance?

What we [my team of researchers] can contribute is that we are looking into the very early phases of drug resistance. This is the focus of our research. What we’re doing is looking into early drug resistance using a cell-based model. Then, we are actually exposing the cell in the cell culture to combination therapy and then we’re looking at what’s happening to the cells—how they’re developing, how they’re changing their phenotype, and how they’re changing in the epigenetic box. This is important because we think, within the first 2 to 3 months, all of the changes you’re seeing are epigenetic changes—not necessarily mutation-induced changes.The final goal would be either to make melanoma a chronic disease or even have the oncologists really be able to eradicate the tumor. What we came out here to do was to have a closer look at the early stage of drug resistance and how we can find some new targets that can be combined with already existing different combination therapies.What’s happening, especially if you’re talking about targeted therapy, is that you have a compound that is directed toward the signaling pathway that is hyper-activated. If you inhibit that, it has been shown in many studies already that this is only working for a certain time and the cancer cell will actually develop new kinds of pathways that they can use for survival. At the same time, what we see if we stress the cells with a BRAF inhibitor or MEK inhibitor and we are introducing stress is an epigenetic profile.

This opens a window where we can either— from the beginning—add another or add another treatment later on, so that the cells cannot adapt to stress. If they’re not adapted to stress because they’re not changing the epigenetic phenotype, then it could be a good way to get better survival.

How do you know what to add and when?

This has been tried in the past. However, it depends on how you apply it and which drugs you use in addition to already existing drugs.That’s a critical question, and it’s what we’re all hunting for. We do not know at the moment when you would start with that. This is a part of our research where we’re also interested to know when we should add this drug and what’s the best time point to really diffuse the drug tolerance.

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