A new type of experimental anti-cancer drug developed by Genentech, which inhibits the hedgehog signalling pathway, was effective in treating patients with advanced skin cancer. It was also very effective at first in treating a patient with an advanced type of brain cancer, and initial results were dramatic, but after a few months the cancer became resistant to the drug. Nevertheless, experts suggest the findings open a route to new types of drugs for fighting cancer that shut down the gene signalling pathways that spur tumor growth.

Three papers about the effectiveness of the new drug have been published in the last few days, two in the New England Journal of Medicine and one in Science.

One of the NEJM papers describes a promising trial where the safety and antitumor activity of the experimental hedgehog inhibitor drug was tested on patients with advanced and inoperable basal-cell carcinomas, and the other NEJM paper reports using the drug to treat a patient with a very advanced metastatic medulloblastoma (a type of brain cancer) where the effect was dramatic but did not last.

The Science report decribes a genetic investigation into what happened with the brain cancer patient, and found that certain acquired mutations in a key receptor can lead to drug resistance in human cancer.

The drug referred to in all three studies, which were supported by funds from the company, is Genentech’s experimental drug code named GDC-0449 that blocks the hedgehog signalling pathway, a new and exciting field of development for cancer treament.

The hedgehog molecule, which exists in organisms ranging from flies to humans, controls the signals that cells need to grow properly, and is active from embryo through to childhood. It is supposed to switch off in adulthood, but if it doesn’t, it can promote cancer.

In the first NEJM paper, Dr Daniel D Von Hoff, from the Translational Genomics Research Institute and Scottsdale Healthcare in Scottsdale, Arizona, and colleagues described how basal-cell carcinoma is often characterized by mutations in two hedgehog pathway genes: PTCH1 (patched homologue 1) and SMO (smoothened homologue).

Basal-cell carcinoma is the most common type of skin cancer and affects about 1 million Americans a year. It is rarely fatal but it can cause severe disfigurement and should be treated straight away.

For their study, which was a phase 1 clinical trial, Von Hoff and colleagues assessed the safety and workings of GDC-0449, which they described as a small-molecule inhibitor of SMO, as a treatment for metastatic (already spreading to other sites) and locally advanced basal-cell carcinoma in 33 patients.

Each patient received one of three oral doses of GDC-0449. 17 patients received 150 mg a day, 15 received 270 mg a day and 1 patient received 540 mg a day.

After a median treatment period of 9.8 months, the results showed that:

  • 18 of the 33 patients had an objective response to the drug: 2 had a complete response and 16 had a partial.
  • These responses were assessed from imaging (7 patients), physical exam (10 patients) or both (1 patient).
  • The 15 other patients of the 33 were assessed as having either stable (11 patients) or progressive (4) disease.
  • There was evidence of hedgehog signaling in tumors that responded to the treatment.
  • 7 patients showed adverse events, 6 of which were possibly related to the study drug. One patient withdrew from the trial because of adverse events.

The researchers concluded that:

“GDC-0449, an orally active small molecule that targets the hedgehog pathway, appears to have antitumor activity in locally advanced or metastatic basal-cell carcinoma.”

In the second NEJM paper, Dr Charles M Rudin of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, and colleagues, wrote that abnormal activation of the hedgehog signalling pathway is thought to play a key role in the development of some cases of medulloblastoma, the most common malignant brain tumor in children.

They reported the case of a 26-year old man with medulloblastoma that had spread to other sites in his body and was resistant to several types of therapy, including radiation and chemotherapy. He had also had extensive surgery. When the researchers analysed specimens of his tumor tissue they found evidence that the hedgehog pathway was active.

After treatment with GDC-0449, scans showed that the man had surprisingly fewer tumors and he also experienced fewer symptoms and gained a little weight. However, within a few months of starting the new drug, the cancer became resistant to it and the man died.

The authors wrote that:

“Identifying the mechanisms of acquired resistance to selective hedgehog pathway inhibitors in patients with medulloblastoma will be of particular interest in future studies.”

They commented that using an inhibitor that targets a pathway that is clearly involved in developing malignant tumors in medulloblastoma may be a better treatment option than those currently available, and it may avoid some of their side effects.

However, they caution that the hedgehog pathway regulates several growth processes, and although initial tests with adults show “acceptable” side- effects, this may not be the case with children, who may experience skeletal growth complications on both cartilage and bone.

“Cautious application of these initial observations through carefully monitored clinical trials involving a broad spectrum of patients with medulloblastoma is warranted,” wrote Rudin and colleagues.

In the Science paper, Robert L. Yauch, from Genentech, South San Francisco, California, and colleagues, some of whom also worked on both the NEJM studies, investigated what happened in the case of the single medulloblastoma patient whose cancer became resistant to GDC-0449 after showing such a dramatic initial response.

They looked at the state of the hedgehog signalling genes in the tumors after they had been treated and the disease had started progressing again. The found an amino acid in the SMO gene that had no effect on the hedgehog signalling but disrupted the ability of the drug to bind to SMO and suppress the signalling.

To double check their finding, they found the same amino acid occurred in mice bred with medulloblastoma that also showed resistance to GDC- 0449.

Yauch and colleagues concluded that certain acquired receptor mutations can “serve as a mechanism of drug resistance in human cancer”.

In an editorial accompanying the NEJM papers, Drs Andrzej A. Dlugosz and Moshe Talpaz, wrote:

“These studies require that we learn much more about the safety and efficacy of GDC-0449. Nonetheless, the remarkable responses that are reported in the initial cases suggest that the hedgehog pathway can be the basis of an important new class of therapeutic agents with far-reaching implications in oncology.”

“Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma.”
Von Hoff, Daniel D., LoRusso, Patricia M., Rudin, Charles M., Reddy, Josina C., Yauch, Robert L., Tibes, Raoul, Weiss, Glen J., Borad, Mitesh J., Hann, Christine L., Brahmer, Julie R., Mackey, Howard M., Lum, Bertram L., Darbonne, Walter C., Marsters, James C., Jr., de Sauvage, Frederic J., Low, Jennifer A..
N Engl J Med Published online 2 September 2009.
DOI: 10.1056/NEJMoa0905360

“Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449.”
Rudin, Charles M., Hann, Christine L., Laterra, John, Yauch, Robert L., Callahan, Christopher A., Fu, Ling, Holcomb, Thomas, Stinson, Jeremy, Gould, Stephen E., Coleman, Barbara, LoRusso, Patricia M., Von Hoff, Daniel D., de Sauvage, Frederic J., Low, Jennifer A.
N Engl J Med Published online 2 September 2009.
DOI: 10.1056/NEJMoa0902903

“Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma.”
Robert L. Yauch, Gerrit J. P. Dijkgraaf, Bruno Alicke, Thomas Januario, Christina P. Ahn, Thomas Holcomb, Kanan Pujara, Jeremy Stinson, Christopher A. Callahan, Tracy Tang, J. Fernando Bazan, Zhengyan Kan, Somasekar Seshagiri, Christine L. Hann, Stephen E. Gould, Jennifer A. Low, Charles M. Rudin, and Frederic J. de Sauvage.
Science, Published online 2 September 2009.
DOI: 10.1126/science.1179386

Written by: Catharine Paddock, PhD