Synthetic lethality as a basis to select drug combinations

Share :
Published: 4 Jul 2017
Views: 2316
Prof René Bernards - Netherlands Cancer Institute, Amsterdam, Holland

Prof Bernards speaks with ecancer at WIN 2017 about a staggered '1-2 punch' treatment schedule of cancer therapies, built on synthetic lethality.

In the case of BRAF melanoma, he describes the acquired MEK-resistance of tumour cells following initial treatments exposes vulnerability to histone deacetylases (HDAC) which generate a toxic level of reactive oxygen species (ROS) in cancer cells.

Prof Bernards outlines how intermittent dosing cycles with short HDAC therapies 'chasers' may prevent further resistance development and extend patient survival.

He goes on to explain the best treatment window for selectively targeting cancer cells follows an induced senescence, with animal models currently in development.

My laboratory in Amsterdam has been working for a number of years on highly effective drug combinations that we identify through synthetic lethal interactions. These are then interactions where two pathways that are inhibited together are far more powerful than each individual pathway when it’s inhibited as a single target. That has worked very well and we think that some of the combinations that we have identified will get approved within the next year but what we might want to do is try something completely new in the field of oncology.

I’m going to talk about that today which I call the one-two punch model for cancer treatment. It is not based on simultaneous treatment with two drugs but on sequential treatment with two drugs. The concept behind this is that the first drug is given with the intent to expose a major vulnerability in the cancer cell that is then exploited and targeted by the second drug. That is, in boxing, the concept of the one-two punch – you hit on one side and you hit somewhere else and then your opponent falls down. I am not a violent person and I don’t box myself but I thought that this concept could be applied to oncology because oncologists are used to the notion that the first drug you apply is the most powerful one and the second and the third line drugs become less and less effective. But I don’t think they necessarily have to be, it can be potentially that a second line therapy is more effective than a first line if the vulnerability that is created by drug resistance to the first drug is greater than the original vulnerability of the cancer cell. So I’m going to illustrate that today with the case of BRAF mutant melanoma.

We all know that those patients are treated with combinations of BRAF and MEK inhibitors and they respond typically very well but then they become resistant and they become resistant through a hyper-activation of the MAP kinase pathway. The question that we asked is is there a vulnerability associated with hyper-activation of the MAP kinase pathway that we could exploit in a subsequent treatment once the patients have become resistant to the BRAF plus MEK inhibitor combination. The answer that we found is that there is indeed such a vulnerability and that is that the cells that become BRAF/MEK resistant have significantly upregulated the concentrations of reactive oxygen species in the cancer cells, ROS. Now the cells are not unable to deal with that, with those higher ROS levels, so they are viable and they live but the ROS levels are significantly increased. Then we found that a little used anti-cancer drug called vorinostat, a histone deacetylase inhibitor, also increases the reactive oxygen species levels in cancer cells and we asked the simple question are the elevated ROS levels that are induced by the resistance to the BRAF/MEK, if you superimpose on that a further increase with an HDAC inhibitor like vorinostat is that now a lethal concentration of ROS. The answer is that it is. So while parental melanoma cells that have much lower levels of ROS are able to deal with the increase that is induced by HDAC treatment, the BRAF/MEK resistant cells are unable to treat so they are selectively killed. So while parental melanoma cells that are drug BRAF/MEK sensitive are resistant to the HDAC inhibitor, the BRAF/MEK resistant cells become highly vulnerable to the HDAC inhibitor. And that’s exactly what we were trying to find – an acquired vulnerability of BRAF resistant cells.

In fact we have taken this to the clinic and what I will show today in a first few patients is that we can selectively kill the BRAF/MEK resistant cells in the patients when we switch them to an HDAC inhibitor, providing proof of concept for that notion that we can actually kill drug resistant cells by targeting their vulnerability.

What success rates are you looking at?

In the end we probably want to take this treatment to an earlier stage of cancer where we don’t wait until the patient has become fully resistant. But my current thinking goes in the direction that we should actually treat the patient with BRAF/MEK and then for a short period in an intermittent way dose a high concentration of HDAC inhibitor to select or to selectively kill any insipient resistant cells. That treatment probably doesn’t need to be very long and then you can switch back to your BRAF/MEK. If you do that intermittently we’ve known that we have already seen that intermittent dosing with a drug holiday in the past is not a good idea but if you do an intermittent dosing with an HDAC in the break of the BRAF/MEK where the HDAC now selectively kills the resistant cells, that has a very good chance of being successful and prolonging overall survival for these patients.

A small shot to kill any incipient resistant cells up front because we have shown that the HDAC, in fact, can eradicate completely the resistant cells from a large population, from a large nodule of resistant cells in a patient where only the drug sensitive parental cells remain. That is in a relatively short period of time.

Are there any plans for future studies?

Yes, absolutely, and that’s the second part of my talk where we are asking the question can we make this a general approach beyond BRAF mutant melanoma. That begs the question is there a general vulnerability that we can induce in all cancer cells and the only one that I’ve been able to come up with is senescence. Senescence is a state of post-replicative proliferation arrest that is stable and it’s associated with significant changes in metabolism, gene expression, chromatin structure. Therefore I would have thought that you could actually kill senescent cells relatively easily and indeed there are a number of publications out there that are what they call so-called senolytic agents, agents that kill senescent cells selectively.

So this begs then the question are there drugs that allow us to induce senescence in cancer cells as a first punch in the one-two punch model where the first punch is induction of senescence and the second punch is to kill the senescent cancer cells. What I will show in my presentation this afternoon is that we have set up genetic screens, functional genetic screens, with CRISPR-Cas9 based technology to find genes whose inactivation causes senescence in cancer cells. We can exploit that knowledge of which pathways we need to inhibit to trigger senescence to now treat patients with a tumour with a drug that induces senescence and then we can selectively ablate those senescent cancer cells with a second drug. I’ll show you proof of concept for that in cell culture models and we’re currently working on the animal validation of that concept.

It is well established that senescent cancer cells secrete a lot of cytokines, they call that the senescence-associated secretome, interleukin cytokines. Typically senescent cells attract a lot of immune infiltrate so it provokes an inflammatory reaction which typically is used to clear out the senescent cells from the body. So if you attract a whole range of inflammatory cells to a cancer that has at least partially become senescent you could imagine that a combination with a checkpoint immunotherapy could be highly beneficial to those patients. So that is certainly something that we need to look at in the future.