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Drugs of interest to pathologists

Drugs related to surgical pathology

Vismodegib


Author: Him G. Kwee, M.D. (see Reviewers/Authors page)
Revised: 27 April 2012, last major update February 2012
Copyright: (c) 2012, PathologyOutlines.com, Inc.

General
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● An artificial inhibitor of the hedgehog signaling pathway

Trade name
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● Eviredge®

Clinical information
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Approved by US Food and Drug Administration on January 30, 2012 for:
● Metastatic basal cell carcinoma or locally advanced basal cell carcinoma in adults that has relapsed after surgery, or that cannot be treated with surgery or radiation (Erivedge.com)
● Abnormal hedgehog signaling is implicated in more than 90% of basal cell carcinoma cases
● Vismodegib is an antagonist of the smoothened receptor (SMO) of the hedgehold signaling pathway
● Cost estimate: $7,500 a month (San Francisco Chronicle, January 31, 2012)
● Clinical trials are underway studying vismodegib in metatatic colon cancer, small cell lung carcinoma, metastatic stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma

Clinical side effects
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● Vismodegib is embryotoxic and teratogenic in animals; teratogenic effects included midline malformations, missing digits and other irreversible malformations
● The drug should not be used during pregnancy
● Female patients that could become pregnant should be advised of the need of contraception up to seven months after the drug is discontinued
● Male patients using the drug should be advised of the risk of exposure to their female partners through semen, even after vasectomy, up to 2 months after the drug is discontinued
● Patients on this drug should not donate blood or blood products up to seven months after the drug is discontinued
● It is not known whether the drug is excreted in breast milk, but it has the potential to cause serious side effects to the nursing infant
● Side effects include muscle spasms, alopecia, anorexia, weight loss, diarrhea, constipation, dysgeusia / ageusia, fatigue, arthralgia, hyponatremia, hypokalemia or azotemia (Thomson Reuters, Vismodegib, June 2011)

Molecular theory
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● The hedgehog signaling pathway is one of the key regulators of animal and human development; it gives embryonic cells information that they need to make the embryo develop properly
● Aberrations may cause spontaneous abortion or severe fetal malformations such as holoprosencephaly and cyclopia
● The pathway is normally inactive in differentiated cells, but is important to regulate adult stem cells involved in maintenance and regeneration of adult tissue
● The hedgehog signaling pathway comprises three ligands, Sonic (SHH), Indian (IHH), and Desert (DHH) and two interacting transmembrane receptors, Patched (PTC) and Smoothened (SMO)
● In the absence of ligand binding, PTC and SMO form a repressive complex that inhibits cell proliferation
● Abnormal activation of the hedgehog pathway, such as via mutations, leads to development of disease through transformation of adult stem cells into cancer stem cells
● Activation of the hedgehog pathway increases angiogenic factors (angiopoetin-1 and angiopoetin-2), cyclin D1, cyclin B1 and anti-apoptotic genes and decreases apoptotic genes (Fas, Wikipedia)
● Activation of the hedgehog signaling pathway may be implicated in the development of basal cell carcinoma, prostate cancer, breast cancer, medulloblastoma, rhabdomyosarcoma, pancreatic cancer, stomach cancer, colon cancer, gliomas, leukemia, lymphoma, melanoma and probably other malignancies

End of Drugs > Drugs related to surgical pathology > Vismodegib


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