New inhibitor prevents lesions and reduces tumour size in basal cell cancer

Bookmark and Share
Published: 20 Apr 2011
Views: 6470
Dr Ervin Epstein - Children's Hospital of Oakland Research Institute, California, USA
A new hedgehog pathway inhibitor demonstrated efficacy in preventing and treating basal cell cancer among patients with basal cell nevus syndrome, a rare inheritable disease. It is known that basal cell nevus syndrome is caused by a mutation in the PTCH gene, which encodes a primary inhibitor of the hedgehog signalling pathway. Using this information, researchers developed the anti-hedgehog signalling pathway drug GDC-0449.

Dr Ervine Epstein discusses the extremely positive results of a Phase I trial which demonstrated that GDC-0449 significantly reduced the size of existing basal cell carcinomas and the development of new carcinomas. Although many skin cancers can be successfully treated with surgery, this therapy would be very useful for treating patients with many basal cell carcinomas.

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

New inhibitor prevents lesions and reduces tumour size in basal cell cancer

Dr Ervin Epstein (Children’s Hospital of Oakland Research Institute, California, USA)

Ervin, you’ve been talking about hedgehog signalling, a fascinating mechanism. I don’t fully understand hedgehog signalling but…

Neither does anyone else.

I gather it’s very important for basal cell carcinoma; can you tell me why this is important and what you’ve been doing about that fact?

The story really goes back to 1980 when people identified a number of genes important in fruit fly development, the process by which a single fertilised egg turns into a normal adult. And one of those was the hedgehog signalling and the PTCH gene was identified as an inhibitor of that signalling pathway. In 1996 two groups identified the PTCH locus, the PTCH gene locus, as the site of mutations that underlie a rare heritable disorder that had been described last by Robert Gorlin and so was known as the Gorlin syndrome. They have a host of phenotypic abnormalities, most prominent of which is the development of many basal cell carcinomas. So 99.9% of people who develop these cancers get them sporadically, get one or two, but these people get large numbers.

So you’ve been looking at basal cell carcinoma which is the commonest human cancer, I believe, but you’ve actually been looking at a very rare type of it?

We looked at a very rare type because prior to that there was really no way of understanding the molecular abnormalities in this most common of human cancers because they don’t grow in tissue culture, they don’t grow on mice and there is no mouse model.

You found that hedgehog signalling was abnormal in these particular patients, what next?

What next was to find that it’s abnormal in all basal cell carcinomas; it’s pivotal to basal cell carcinoma genesis. So most recently, because hedgehog looks to be important perhaps in visceral cancers as well, there has been a flood of agents from different pharmaceutical companies that are developed to inhibit this signalling pathway.

Now you’ve been looking at GDC0449 and you’ve reported a study here at the AACR, can you tell us a little bit about that please?

That’s right, the first in man is this GDC0449 of the hedgehog inhibitors. So we took patients with this rare disease who have a mutation in this PTCH gene and therefore have lots of hedgehog up-regulation and we gave them the hedgehog inhibitor. The use of these people is better than using people like you or me who have sporadic basal cell carcinomas because they get many, many basal cell carcinomas over a short time.

And what did you find?

We found that it was spectacularly successful in number one, inhibiting the development of new BCCs, essentially the patients, as soon as they started on it stopped getting new BCCs whereas those on placebo we saw almost 700 new BCCs in our population on placebo. Number two, the larger BCCs that they had all melt away and in fact we saw no evidence of any resistance in any of the tumour lesions that they had.

So you’ve got good treatment, it seems, for skin cancer but then skin cancer is easy to treat anyway.

For sure, 99% now in the best of hands, surgical hands, can be cured by surgery but there are some that can’t be cured by surgery and for these people who get many, many basal cell carcinomas it could be a godsend in terms of reducing the need for surgical excisions every several weeks.

So what is the practical message, the outcome from this study, do you think, in terms of busy cancer doctors?

The first lesson is for those rare patients with this condition there is real hope that something can be done for them other than an indefinite no light at the end of the tunnel series of surgeries. But the second is that since this works so well it certainly should stimulate other approaches that also inhibit hedgehog for the use in sporadic basal cell carcinomas. Now there’s a high bar to get over because, as I said, 99% are cured now but some aren’t and, of course, if we had a cream to rub on or a pill that one could take without much side effects for a brief time most people would opt for that instead of surgery.

Do you think there are possibilities of applying this principle in other cancers?

I think this study is really a poster child for the success of understanding molecular defects in cancer, developing a drug that reverses those molecular defects and seeing a spectacular result. So it’s equivalent or similar to Gleevac for CML, or at least it appears that way now.

So do you see hedgehog signalling moving centre stage?

Five years ago we might have said yes, it looks like it’s important in 25% of all cancers. I think most people don’t think it’s as important in that many cancers but I think there will be some systemic cancers where hedgehog will be centre stage for at least some patients. And so I think it does suggest that there will be hope for those patients as well.

So what’s the bottom line message for cancer doctors?

The bottom line message for cancer doctors is hope is on the way.

Dr Epstein, it’s a pleasure to see you again. Thank you for joining us here on

Thank you very much.