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

New target identified for squamous cell lung cancer

Professor Matthew Meyerson – Dana Farber Cancer Institute, Boston, United States

Matthew Meyerson, Dana Farber Cancer Institute, you’ve got a new way of treating lung cancer; now that’s pretty amazing because we’ve heard about some of the molecular approaches that are suitable for non-squamous cell, non-small cell lung cancer but you have now got something for squamous cell cancer, haven’t you? Can you tell me what it’s all about?

Absolutely, we have a first step on the path to thinking about a treatment for squamous cell lung cancer. Squamous cell lung cancer accounts for about 30% of non-small cell lung cancers and it’s not really been susceptible to any of the targeted therapies that are out there to date.

Why?

A lot of the effective targeted therapies, EGFR therapies and ALK therapies are basically only for genomic lesions that are present in lung adenocarcinoma, and those lesions the EGFR mutations, the ALK translocations, aren’t there in squamous cell lung cancers.

Now can you tell me a little bit about this DDR2 mutation, because that’s the key, isn’t it?

Absolutely. DDR2 is another tyrosine kinase, like EGFR and ALK, and we were looking for tyrosine kinase mutations in squamous cell lung cancer because we wanted to find new drug targets. And we found the mutations in DDR2, they’re in about 4% of squamous cell lung cancers.

Can you tell me about the study that you presented here today at the American Association for Cancer Research, and you’ve just published it, of course?

It’s just published in a new journal called Cancer Discovery, the journal of the American Association for Cancer Research, and the study is led by a young medical oncologist in my group, Peter Hammerman, who has directed the bulk of these studies.

What did you do and what did you find?

We were sequencing protein kinases and we found about 4% of squamous cell lung cancers have mutations in DDR2. Then we asked, are there drugs that block DDR2 and, if we look at squamous cell lung cancer cell lines that have DDR2 mutations, can they be killed by these drugs? It turned out the answer to both those questions was yes. First of all, the drug dasatinib is effective at inhibiting DDR2 and second, squamous cell lung cancer cell lines that have DDR2 mutations are killed by dasatinib.

Because it’s very interesting that dasatinib does the job but it’s a proof of principle as well, isn’t it?

Absolutely, it’s a proof of principle but the exciting thing about dasatinib is it’s already in clinical use for chronic myeloid leukaemia so that means it should be relatively straightforward to imagine how to test it in squamous cell lung cancer patients.

What do you think needs to be done now then?

I think it would be great if a clinical trial could be started of dasatinib in squamous cell lung cancer. One of the pieces of that with the trial is to develop a method of testing patients for DDR2 mutations and potentially for other targets of dasatinib.

You’ve got a new target, then, for squamous cell lung cancer, what should doctors be making of this discovery and what are the hopes?

The hope is that just like in lung adenocarcinoma, where we can start to sub-set the patients and start to find effective treatments, at least for some duration, for lung adenocarcinoma there is hope that we can start bringing similar targeted therapies to squamous cell lung cancer.

You said that this is present in 4% of patients.

That’s right.

Presumably there could be other targets, do you think there could?

There could be and we know of some other targets but there are no approved drugs yet for those targets. Two other targets are FGFR1, which is often amplified in squamous cell lung cancer, that’s also a tyrosine kinase, and then the PI3 kinase gene, PIK3CA, is mutated in several per cent of squamous cell lung cancers. FGFR inhibitors and PI3 kinase inhibitors are both now in clinical trials, none of those have yet been approved for treatment. But if we add up the idea of inhibiting FGFR, inhibiting PI3 kinase and inhibiting DDR2, now we’ve got a significant fraction of squamous cell lung cancer patients.

And lung cancer is one of the commonest cancers in many countries and certainly one of the most lethal. How much might this change the picture in terms of therapy, improving therapy, in that one-third of patients who do have squamous cell, non-small cell lung cancer?

I think it would obviously make a very big difference for those patients and there are a lot of people with this disease – there are more than a million people who die worldwide every year from lung cancer, probably several hundred thousand of those people have squamous cell lung cancer. So if you’re looking at a third of squamous cell lung cancers, that’s probably tens of thousands of patients around the world, a lot of people who would have the opportunity to benefit from these new treatments. With the important caveat, if these treatments prove beneficial because right now there is good evidence for the hope but there is no evidence for the efficacy.

You’ve had it in xenografts, haven’t you?

That’s right, we’ve done xenografts of the tumours from these cell lines and the xenografts are also treated effectively by the drug. Again, it’s not the same as treating the patient with the cancer. There was also one patient on a clinical trial who responded this time to a combination therapy – dasatinib plus erlotinib. They didn’t have EGFR mutations that would make sensitivity to erlotinib but the patient’s cancer did have a DDR2 mutation that could explain the sensitivity to dasatinib. So we may have a good explanation for the dasatinib response but again it’s only in one patient.

And are there a lot of TKIs out there ready to treat some of these molecules when they’re found?

There are a lot of TKIs that are out there but most of them are in relatively early clinical trials and therefore they are not yet approved for therapy. So I think there’s a lot of work to generate the trials and find the right data. And an important point I would like to make is I think there are a lot of effective TKIs out there that have not yet been shown to be effective because the right clinical trials haven’t been done. The clinical trials aren’t always selective enough and it’s important to do the more highly selective trials.

So what messages, briefly, would you give to cancer scientists and, of course, cancer clinicians coming here from your presentation at the AACR annual meeting?

My first conclusion would be to start thinking about targeted therapies for squamous cell lung cancer; to start thinking about sub-setting those patients and to start thinking about identifying ways in which patients might benefit from new targeted therapies and ways that those trials can be developed. And for the cancer scientists, the basic scientists, ways to understand the biology of squamous cell lung cancer so that we can classify the disease and we can see what are the pathways in which drugs might act.

And of course overcome some of the feeling, sometimes, of futility and hopelessness that both doctors and patients sometimes feel about this disease.

Absolutely, I think that these new data really provide a lot of help for patients and for their treating physicians.

Dr Matthew Meyerson, thank you very much for joining us here at ecancer.tv.

Thank you very much.

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