Combination therapy targeting MEK and PI3K pathways shows anti-tumour activity

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Published: 20 Apr 2011
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Dr Johanna Bendell - Sarah Cannon Research Institute, Nashville, USA
The combination of two compounds that inhibit two of the most frequently mutated cancer pathways is showing promise in an ongoing Phase I trial. The research, presented by Dr Johanna Bendell, tests a combination of GDC-0973, which inhibits MEK1/2 and GDC-0941, which inhibits PI3K. The patients received a combination of different doses of GDC-0973 and GDC-0941; these drug combinations were well tolerated and only produced with mild side effects. Several patients demonstrated decreases in tumour size, including two patients with melanoma, one with prostate cancer and two with non-small cell lung cancer. It is hoped that these targeted treatments will eventually help clinicians treat cancers more effectively and will produce fewer adverse effects than current therapies.

AACR 102nd Annual Meeting, 2—6 April 2011, Orlando, Florida

Combination therapy targeting MEK and PI3K pathways shows anti-tumour activity

Dr Johanna Bendell (Sarah Cannon Research Institute, Nashville, USA)

It’s great to talk with you, Johanna, because you’ve been looking at blocking two pathways, these are molecular pathways, to inhibit tumour growth. It sounds very exciting and a very refined way, what have you been doing? Tell us about the study.

Well we’re so excited because we think that the future of cancer therapy comes to attacking cancer cells for what makes them cancer cells. When you look at traditional chemotherapy agents, they kill rapidly dividing cells so we have a certain amount of toxicities that we all know come along with chemotherapy. But if we can actually strike at the heart of cancer cells, what makes them particularly abnormal, we might be doing better at targeting those cancer cells specifically. So what we’ve done now in the future of cancer research is to attack specific pathways that we find are abnormal in cancer cells. What we’ve done is not only now attacked each individual pathway, but we’re attacking two pathways together.

What’s special about the PI3 kinase and RAS/RAF/MEK pathways? To start with, what are they?

These are two pathways that send signals throughout the cell that tell them to divide. In normal cells those are activated but we turn them back off again; in cancer cells they can be activated to the point where we can’t turn them back off again and cause those cells to grow and grow and form cancers.

But you’ve got some drugs that do do the turning?

Exactly, so the PI3 kinase pathway and the RAS/RAF/MEK pathway are two of the most abnormal pathways that are in a substantial number of cancers activated abnormally. So we have two individual agents that block each pathway specifically.

So what did you do in the study

The aim of the study was to actually see if we could safely block two pathways in cancer patients and then if we could safely do so did we see any preliminary signs of anti-tumour activity?

And what happened?

What we saw is indeed we can combine the two agents safely. When we look at the toxicity profiles that were seen, they were very similar to each agent alone and then we’ve actually also seen some preliminary signs of anti-tumour activity as well.

Now is this a long way from the therapeutic armoury or could it perhaps indicate how cancer doctors could be treating their patients soon?

I think that what we will be looking at is this is not too far in the future; many companies are very excited about this approach, there are other studies that are currently on-going. I think that we are starting to learn that this is the way we need to go in cancer therapy, so I can only assume that this is going to try to come into the clinic as quickly as possible.

Could you give me some idea, though, of how effective this dual blocking action was and which sorts of patients? It was a wide range of cancers, wasn’t it?

Yes. We only looked at thirty patients in this particular report and when we looked at preliminary signs of efficacy we saw some in melanoma patients, we saw some in non-small cell lung cancer patients but these are very preliminary signs of anti-tumour activity. What is going to be the next step is to actually look in specific cancers and to try to get more of a sense of who these combination targeted therapies will help.

And are there other molecular pathways that you could potentially target and perhaps refine the process even further?

Absolutely positively. Most of the cancer research now is looking for more of these pathways because these pathways not only cause problems in and of themselves but they interact with each other. So there are going to be more and more trials that you are going to see combining agents that are targeting multiple different pathways to try to get ahead of the cancer.

Obviously it’s an evolving story but what would you like cancer doctors to remember from this in practical terms for their treatment in the here and now?

I think that we’re entering a new era in cancer treatment where we’re really specifically going after the cancer, where we’re going to be able to shut down a cancer for what it is and we’re going to hopefully spare our patients a lot of side effects that we usually see with chemotherapy.

Dr Johanna Bendell, thank you very much for joining us here on

Thank you so much.