Vice President, Molecular Biology
Why is the Hedgehog pathway important in basal cell carcinoma and medulloblastoma? "We believe that the Hedgehog pathway is important in cancer and more specifically in basal cell carcinoma, which is a very common form of skin cancer, and medulloblastoma, which is a form of brain cancer most common in children, because of the discovery of mutations in components of the Hedgehog pathway and in particular of the receptors of Hedgehog which are molecules called patched and smoothened. The mutation in smoothened was actually discovered at Genentech. A mutation in a component of the Hedgehog pathway leads to aberrant activity of the pathway and therefore suggests that it should be possible to develop inhibitors of the pathway which if they act downstream of this mutation should be beneficial for the treatment of these cancers."
Jennifer Low, M.D., Ph.D.
Global Clinical Lead, GDC-0449
What are the findings of the Phase I trial for GDC-0449, an oral small molecule inhibitor of the Hedgehog signaling pathway, in skin cancer? "The first trial with GDC-0449 began a couple of years ago to find the right dose as the first step in developing a new drug for cancer. Luckily for us in this Phase I trial, our first patient had an extremely rare disease, metastatic basal cell carcinoma, and even better, his tumors began shrinking within a few months of being on study. We knew from research that the Hedgehog pathway is important for basal cell carcinoma and so after seeing shrinkage of this tumor we immediately opened up another cohort to look at patients with advanced basal cell carcinoma and to determine how effective GDC-0449 would be in these patients. We were really thrilled to see that we had a response rate of more than fifty percent."
How common is basal cell carcinoma and how is it typically treated? "Basal cell carcinoma is actually one of the most common malignancies in people, about a million cases a year. It's generally a very treatable disease, usually handled with a surgical procedure. But for the very small number of people whose disease spreads, it can't actually be managed through surgery and for those people there is no approved therapy."
What is the significance of the case study in medulloblastoma? "Medulloblastoma is a brain cancer that is seen in children and young adults. The mutation that occurs in some forms of medulloblastoma is actually the same mutation in the Hedgehog pathway that we see in basal cell carcinomas. In our Phase I study we had a young adult who had medulloblastoma and we saw significant tumor shrinkage with GDC-0449. These results are really important because it is the first time that we are showing a Hedgehog pathway inhibitor being able to affect this disease."
What is Genentech's clinical development program for GDC-0449? "We began a study to try to gain FDA approval for GDC-0449 in very advanced basal cell carcinoma. We also have a number of other clinical trials ongoing including trials looking at the effect of a Hedgehog Pathway Inhibitor in colorectal cancer and ovarian cancer. We have ongoing collaborations with a number of partners including the National Cancer Institute to look at other tumor types including medulloblastoma."
Frederic de Sauvage, Ph.D.
Vice President, Molecular Biology
When did you begin research on the Hedgehog signaling pathway? "We started working on the Hedgehog pathway in 1996. It was at a time when the Hedgehog pathway was still a very unknown topic. It was mostly a molecule that had just been discovered in flies. We had the idea that this pathway could be important in cancer because other related pathways had been found to be important in cancer. We started to characterize the mechanism of action of Hedgehog and its potential role in cancer."
Where does the name Hedgehog come from? "The name Hedgehog comes from the initial discovery of the Hedgehog gene in flies when scientists did fly mutagenesis in order to discover new genes and new phenotypes. What they found is one fly strain that had hairs sticking out in all directions instead of being neatly organized like they should be. These scientists were very creative and original and were coming up with all kinds of funny names to describe their mutant and basically this fly with its hair sticking in all directions reminded them of a hedgehog. The name stuck and that gene was called Hedgehog."
What is it like to see a molecule you've worked on in the lab move into the clinic? "Having a molecule you've worked on for a long time making it to the clinic, making it into patients, is really a fantastic feeling. I think this is really a dream for many of the scientists who work in the medical field, and in this case it was really a dream come true. This is especially even more so the first time you get reports that there is potential activity of your molecule and that you potentially have patients responding to your drug, just like what we've reported here in these papers in the New England Journal of Medicine. It's really a dream come true."
What is the significance of the follow-up findings on the medulloblastoma patient that are reported in Science? "In a follow-up study on this patient that was published in the New England Journal of Medicine, this patient with medulloblastoma who relapsed and become resistant to GDC-0449, we have published a study now in Science showing that this patient had actually acquired another mutation in smoothened. Smoothened is the target of GDC-0449 and this mutation now renders the tumor of that patient resistant to the drug, GDC-0449. This is just one patient, this is of course an observation that we will follow up on in other clinical trials and see if this is a general mechanism by which people can become resistant, but this is an important observation as it can really influence the design of future clinical trials or potentially future drug development for molecules that can also potentially target this type of mutation."