Advances in genetic understanding of gorlin syndrome and emerging treatment options

ABSTRACT

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.

KEYWORDS:

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

Article Highlights

• Vismodegib and sonedegib are effective SIs for treating laBCCs, including those associated with BCCNS, but frequently associated with adverse effects.

• In addition to PTCH1 mutations, other genetic etiologies of BCCNS include mutations in SMO and SUFU mutations, which may explain lack of response to SIs in some BCCNS patients.

• Non-Hh pathways may also be involved in BCC pathogenesis in BCCNS and can be potential therapeutic targets, including TP53, BRCA1, PIK3, Wnt.

• Other genetic-based treatments that may be helpful in cases resistant to SI include posaconazole, arsenic trioxide, and taladegib, among many other agents currently under investigation.

• While BCCNS-BCCs have better genomic stability than sporadic BCCs, the former remains susceptible to UV mutagenesis and subsequent resistance to SI therapy.

• A better understanding of calcium and other divalent cation flux as well as intracellular to extracellular concentrations may prove helpful for managing SI-associated adverse effects and understanding SI-resistance.

This box summarizes key points contained in the article.

Declaration of Interests

J Solomon has received honoraria for consultancy from the Gerson Lehrman Group and L.E.K. Consulting. J Solomon has also received honoraria for acting on the advisory board of Samumed, LLC and for speaking for Sun Pharmaceutical Industries Ltd. J Solomon has acted as a Principal Investigator for AbbVie; Allergan, Inc; Boehringer Ingelheim; Cutanea Life Sciences; Dermira; Eli Lilly and Company; Galderma Research & Development, LLC; GlaxoSmithKline; HedgePath Pharmaceuticals, Inc; inVentive Health; Kythera; LEO Pharma, US; Mavis RX PharmaChoice Merck & Co., Inc; Parexel; Pfizer, Inc; Polynoma, LLC; Regeneron; Symbio and UCB. All funds for which J Solomon is an investigator for clinical trials are paid to his employer. J Solomon has also received research funding from Dr Reddy, Archives of Dermatology, Eli Lilly and Company (for Advisory Board work) and NAAF (consultancy). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.