Hedgehog Pathway Inhibition

Abstract

The hedgehog (Hh) signaling pathway is aberrantly activated in a majority of basal cell carcinomas (BCC). Vismodegib and sonidegib are targeted inhibitors of Smoothened (SMO). Both drugs are approved for use in locally advanced BCC (laBCC), with vismodegib also approved for metastatic BCC (mBCC).

Hedgehog pathway activation in T-cell acute lymphoblastic leukemia predicts response to SMO and GLI1 inhibitors

“…Importantly, T-ALL cases with low or undetectable GLI1 expression did not show sensitivity to hedgehog inhibitors, clearly establishing the link between GLI1 expression (as a biomarker for hedgehog pathway activation) and sensitivity to SMO or GLI1 inhibitors. With 2 hedgehog pathway inhibitors being approved by the US Food and Drug Administration for the treatment of basal cell carcinoma, 47 our data warrant further investigation of these drugs for the treatment of T-ALL if our data are confirmed and further extend toward studies with combination therapy.…”

Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy

“…Functional loss of Ptch1 or activating mutations in Smo drive tumorigenesis in BCC and MB mouse models, demonstrating the causative roles of these genes in tumor onset (Goodrich et al, 1997; Hatton et al, 2008; Nitzki et al, 2012; Xie et al, 1998). High frequencies of somatic mutations in PTCH1 (~70-90%), and to a lesser extent SMO (~10-20%), are reported in human BCCs (Bonilla et al, 2016; Sekulic and Von Hoff, 2016). PTCH1 mutations (~45%) and frequent chromosomal loss of the PTCH1 locus are also found in SHH-MB, whereas SMO mutations (~14%) are less common and are highly enriched in adult versus pediatric patients (Kool et al, 2014).…”

“…Although these murine models suggest that Sufu loss alone is not sufficient for tumorigenesis, germline SUFU mutations in both BCC and MB patients strongly indicate that it is indeed an authentic tumor suppressor gene (Kool et al, 2014; Smith et al, 2014). In BCC, SUFU mutations are rare (<10% somatic) (Bonilla et al, 2016; Sekulic and Von Hoff, 2016). In SHH-MB, SUFU mutations occur (~14%), with the majority of these found in infants (0-3 years old) (Kool et al, 2014).…”

Epigenetic markers in basal cell carcinoma: universal themes in oncogenesis and tumor stratification? - a short report

“…While usually considered “low-grade” and “easy” to treat, some BCC subtypes, such as locally advanced BCCs and basal cell nevus syndrome, can be difficult to control surgically [1]. For these tumors, hedgehog pathway inhibitors (vismodegib, sonidegib) constitute the only FDA-approved medical treatment option [1, 2]. However, these inhibitors are associated with only 15–58% response rates and, conversely, 14–30% serious adverse event rates [1, 2].…”