Approval of the first Hedgehog pathway inhibitor for Invasive Basal cell carcinomas
Sixteen years ago, Dr. Anthony Oro was part of the team that discovered the connection between the hedgehog pathway and human cancer. In February 2012, the first hedgehog pathway inhibitor was approved by the FDA. This new drug has been shown to be effective in treating and preventing the most common cancer in the United States, basal cell carcinoma (BCC) of the skin in three independent studies published in the New England Journal of Medicine (NEJM) on June 7, 2012.
The drug, vismodegib (trade name: Erivedge), was tested in clinical trials by Stanford Dermatology faculty in three separate patient groups. The data provided the support for FDA approval February 1. The first study by Stanford Dermatologist Jean Tang evaluated the impact on patients with Gorlin syndrome, a rare disease in which individuals have tens to hundreds of disfiguring BCCs. The second was a separate industry-sponsored study by Dr. Oro and Dr. Anne Chang, and treated non-syndromic patients with locally advanced and metastatic BCCs. Finally, in a study by Drs. Oro and Chang, a new type of genetic mutation leading to severe BCCs was identified. These patients also received treatment as part of their locally invasive BCC study.
The findings for the three NEJM papers demonstrate the effectiveness of vismodegib in treating BCCs whether they are relatively simple, such as with the Gorlin's syndrome patients; or locally advanced; or metastatic. In the Gorlin's syndrome patients, a remarkable 100% of the tumors responded and continued to be inhibited for the duration of treatment. Approximately 40% of the locally invasive and metastatic tumors responded, although secondary resistance to the drug began to develop in this population after about 8 months. More importantly, the studies show the side effects from taking the oral medicine are relatively minimal - hair thinning, taste alteration, and muscle cramps. The treatment success with BCCs opens the door for the use of these Smo inhibitors in other invasive cancers such as medulloblastomas, small cell lung cancer, pancreatic cancer, and prostate cancer.
The studies suggest a bright future for hedgehog pathway inhibitors. In the accompanying editorial in the NEJM, John Lear, a UK dermatologist, relayed the excitement: "It is a landmark day for patients with basal cell carcinoma and all those involved in their care — the greatest advance in therapy yet seen for this disease."
First description of tumor resistance in patients treated with Smoothened Inhibitors
Secondary or acquired resistance of a tumor to a chemotherapeutic agent is defined as regrowth of a tumor after it initially responds to the agent. This is distinct from primary resistance where a tumor never responds to the agent, and indicates that the tumor has evolved in response to therapy. Work from our group this year has found that BCCs from Gorlin’s syndrome patients uniformly respond and thus far, no disease progression or acquired resistance has developed during the treatment period (mean of 8 months). In contrast, treatment of more invasive tumors demonstrates a lower response rate and much higher chance of developing resistance.
In the study by Drs. Chang and Oro published in the Archives of Dermatology on August 20, 2012; 21% of the treated patients developed at least one tumor regrowth while on the drug, with the mean time to detected regrowth at one year. These data indicate that more aggressive tumors display higher initial resistance and are more capable of evolving drug- independent growth characteristics. Our findings point to the need to develop next generation hedgehog pathway inhibitors and develop combination therapies to prevent tumor resistance.
Developing the next generation of hedgehog pathway inhibitors
The emerging tumor resistance while treating advanced BCCs, as well as the early failures of the drug in colon and ovarian cancers highlight the need to develop next generation hedgehog pathway inhibitors to target more downstream portions of the pathway. Our experience in helping develop the first generation drugs provides Stanford investigators with the opportunity to develop and test new leads in house. This includes efficacy and safety testing of the compounds on mouse cancer models, as well as testing initial compounds in early human safety trials. The new Stanford Hedgehog Consortium, a group of eight laboratories, has identified several lead compounds that target the transcription factor GLI. In work appearing in the journal Nature, Dr. Oro’s group has identified a new way that the GLI protein is regulated, and has shown that compounds that block GLI activation can be used to treat resistant tumors.