Going molecular: Translational research brings basic science to bedside

Key Points

National report - Basic research at the molecular level is helping physicians attack diseases including basal cell carcinoma (BCC) and pachyonychia congenita (PC), experts say.

In the former area, a compound called GDC-0449 (Genentech), which inhibits the hedgehog (Hh) pathway that contributes to BCC development, has entered Food and Drug Administration (FDA) phase 2 testing, reports Josina Reddy, M.D., Ph.D., medical director, Exploratory Clinical Development, Genentech.

"In both sporadic and hereditary forms of BCC, there are inactivating PCTH1 gene mutations found in approximately 90 percent of tumors. In the remainder, there are activating mutations in Smo," she says.

Normally, the PCTH1 gene inhibits the function of Smo, which is a signal-transducing protein that signals to the cell nucleus and upregulates the GLI1 transcription factor, Dr. Reddy explains. "We use GLI1 as an indicator of how activated the hedgehog pathway is."

But when a ligand such as sonic, desert or Indian Hh binds to PCTH1, "It relieves this inhibition of Smo, so Smo can then signal to the nucleus to upregulate GLI1," Dr. Reddy adds. If PCTH1 is missing, which happens in many BCCs, "Smo has nothing to regulate it, so it constitutively signals, which also produces upregulation of the pathway."

Cyclopamine

However, GDC-0449 blocks activation of Smo, Dr. Reddy says. "We know that this pathway is druggable because of a naturally occurring inhibitor of Smo," namely cyclopamine, which can cause pregnant ewes to produce cyclopean lambs if ewes consume the corn lily plant containing this substance at a certain point in their pregnancies.

Though GDC-0449 bears no relation to cyclopamine, Dr. Reddy says that in Genentech's development efforts, the company is taking pregnancy precautions similar to those used with isotretinoin and thalidomide.

In a phase 1 dose-escalation trial, investigators gave the drug orally, once daily, to patients with solid tumors refractory to standard treatments. This population included 13 patients with advanced or metastatic BCC, she says. "We also obtained archival tissue to confirm their Hh pathway activity."

"GDC-0449 has a very unusual pharmacokinetic profile, with very high, sustained micromolar plasma concentrations and a long half-life," she says.

Because higher doses didn't produce correspondingly stronger effects, Dr. Reddy says that researchers settled on a 150 mg daily dose. Generally, patients tolerated the drug well, she adds.

As for efficacy, Dr. Reddy says among patients with advanced or metastatic BCC, "We had two patients who had partial responses by solid tumor criteria. We also had patients with metastatic disease that had stabilized" by the study's end. However, one patient experienced rapid disease progression while on the drug.

"In patients with locally advanced disease, we had four partial responses - one of those patients discontinued the drug due to the adverse event of fatigue. We also had several patients with stable disease" at the study's end, and two patients who were not yet evaluable at this point, she adds.

Overall, Dr. Reddy says, "We're very excited about the results we have achieved to date, and we've opened a pivotal phase 2 study in advanced BCC." This single-armed study is enrolling patients with metastatic or locally advanced BCC (not amenable to resection) at a total of 18 U.S. sites, she says. Genentech soon will open similar studies in Europe and Australia, she adds. Additionally, she reports that Ervin H. Epstein Jr., M.D., will open an investigator-initiated study of GDC-0449 in BCNS.