TY - JOUR
T1 - Advances in genetic understanding of gorlin syndrome and emerging treatment options
AU - Shih, Shawn
AU - Dai, Christina
AU - Ansari, Ahmed
AU - Urso, Brittany A.
AU - Laughlin, Amy I.
AU - Solomon, James A.
N1 - Funding Information:
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.
Publisher Copyright:
© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2018/7/3
Y1 - 2018/7/3
N2 - 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.
AB - 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.
KW - Basal cell carcinoma nevus syndrome
KW - complex adaptive system
KW - genetic mutation
KW - gorlin syndrome
KW - hedgehog
KW - orphan disease
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U2 - 10.1080/21678707.2018.1483233
DO - 10.1080/21678707.2018.1483233
M3 - Review article
AN - SCOPUS:85050379241
SN - 2167-8707
VL - 6
SP - 413
EP - 423
JO - Expert Opinion on Orphan Drugs
JF - Expert Opinion on Orphan Drugs
IS - 7
ER -