A pharmaceutical company Genentech, based in San Francisco, California discovered a synthetic drug called Vismodegib, for the treatment of basal cell carcinoma - a type of skin cancer. Vismodegib (Erivedge®) is an investigational medicine designed to selectively target abnormal Hedgehog signaling pathway which is implicated basal cell carcinoma. It represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval.

Need of drug

Basal cell carcinoma (considered malignant) is the most common type of skin cancer in Europe, Australia and the

United States. Most basal cell cancers occur on that part of skin which is most exposed to sunlight or other ultraviolet radiation .It grows slowly and is usually painless. Metastasis or mortality due to BCC is rare. But, it may advance further into surrounding areas such as sensory organs (ears, nose and eyes), bone, or other tissues.If the disease is left untreated or recurs in the same location after surgery or radiotherapy. In some cases treatment with surgery or radiation of advanced basal cell carcinoma may lead to the loss of sensory organs and their functions such as eyesight or hearing.

Proposed Mechanism of Action by Drug

The Hedgehog signalling pathway usually becomes less active as person grows older and functions in maintaining and

repair of tissue. However in some people malfunctions or abnormal activation takes place leading to malignancies. Vismodegib is based on targeted therapy that is to attack the cancer cells without damaging the normal cells thus leading to fewer side effects. Vismodegib inhibits the Hedgehog signaling pathway. In more than 90% of BCC, the Hedgehog signaling pathway is abnormally upregulated. Mutations in key receptor proteins result in abnormal transcription of target genes that regulate basal cell growth and proliferation. Vismodegib acts as an antagonist to prevent transcription factor activation, blocking the signaling cascade.

Adverse Events

In the Phase I clinical trial, adverse events included fatigue, hyponatremia, muscle spasm and atrial fibrillation. No

dose-limiting toxic effects or grade 5 (death related) events were observed during the study period. In the Phase II clinical trial, adverse events included muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss and fatigue. Patients receiving vismodegib were significantly more likely experience adverse events compared to placebo, including hair loss, weight loss >5%, muscle cramps, and taste disturbance. Most adverse events were mild or moderate in severity, and no grade 5 events were observed.

Conclusion

Vismodegib is used to treat aggressive basal cell carcinoma. The addition of this drug to the therapeutic

armamentarium for recurrent, invasive or metastatic basal cell carcinoma gives a new ray of hope to the patients.

Tags: MET Institute of Pharmacy