Advances in genetic understanding of gorlin syndrome and emerging treatment options

作者：Shih Shawn; Dai Christina; Ansari Ahmed; Urso Brittany A; Laughlin Amy I; Solomon James A^*

来源：Expert Opinion on Orphan Drugs, 2018, 6(7): 413-423.

DOI：10.1080/21678707.2018.1483233

• Basal cell carcinoma nevus syndrome
• gorlin syndrome
• genetic mutation
• orphan disease
• hedgehog
• complex adaptive system

Introduction: Basal cell carcinoma nevus syndrome (BCCNS) is a rare syndrome characterized by multiple basal cell carcinomas (BCC), odontogenic keratocysts, and other abnormalities. The most common etiology, the loss-of-function PTCH1 mutations and consequent constitutive hedgehog signaling, can be blocked by smoothened inhibitors (SIs). However, other causes and alternative pathways have been identified.
Areas covered: Vismodegib and sonidegib are SIs approved for treating advanced BCCs and BCCNS-BCCs, but not without adverse effects. Other SIs include itraconazole, SUBA-itraconazole, and paridegib. Their roles in treating resistance to vismodegib and sonedegib warrant further investigation. Inhibition of downstream hedgehog signaling or PI3K by arsenic trioxide, imiquimod, and busparlisib may control SI resistance. Other potential therapeutic targets to control resistance include TP53, BRCA1, wnt, and SUFU.
Expert opinion: BCCNS is more complex than a genetic disease whose consequences result from the predominant PTCH mutation. Other gene mutations, genetic modulation, stromal and surrounding tissue interactions, as well as molecular and electrical chemical constituents contribute to BCCNS being a complex adaptive system with individual and varying presentations in affected patients. Current technology needs to be applied to elucidate the dynamics of disease activity for individual patients.

• 出版日期2018