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  • Immunohistochemical evaluation of gastric cancer tumor sampl

    2022-07-01

    Immunohistochemical evaluation of gastric cancer tumor samples revealed that 57.8% (59/101) were positive for GLI1, and 71.3% (72/101) stained positive for SHH [27]. Overexpression of SHH and GLI1 protein were significantly associated with larger tumor size, tumor aggressiveness, and less differentiation; correlating with a high metastatic potential [27]. Moreover, reduced OS and recurrence-free survival were associated with increased SHH and GLI1 staining [27]; and GLI1 BI-7273 sale was identified as an independent prognostic factor for OS and recurrence-free survival in gastric cancer patients [27]. SHH overexpression has also been reported in 70% of primary pancreatic ductal adenocarcinoma (PDAC) patients, in which paracrine signaling occurs [28]. Immunohistochemical analysis showed that SHH and GLI1 expression were independent prognostic factors in PDAC patients undergoing curative-intent surgery; wherein low expression was associated with improved OS and disease-free survival (DFS) [28]. Logically, therefore, high SHH and GLI1 expression in resected PDAC patients was associated with a poorer prognosis [28]. A meta-analysis determined the prognostic value of GLI1 expression in solid malignancies (ie, breast, digestive tract, liver, pancreatic, and ovarian cancers), which showed an unfavorable impact of increased GLI1 expression on 3-, 5- and 10-year OS and DFS [29]. Furthermore, increased nuclear, but not cytoplasmic, GLI1 expression correlated with a worse prognosis [29]. In BCC, aberrant HH signaling is associated with sporadic mutations in PTCH in >85% of cases and in SMO in approximately 10% of cases [30]. Furthermore, GLI1 is overexpressed in BCC and was reduced by at least 90% following 9 and 17 weeks of HHI therapy [31]. Additionally, newly diagnosed acute promyelocytic leukemia patients showed a significant increase in the expression of several HH signaling pathway components compared with normal controls, including GLI1 (3.6-fold change, P <0.01), GLI2 (2.1-fold change, P <0.05), PTCH (7.8-fold change, P <0.01), and SMO (2.0-fold change, P <0.001) [32]. Understanding the role aberrant HH signaling plays in various cancer types, therefore, provided a rationale for investigation into the potential of hedgehog inhibitor (HHI) therapy in their treatment.
    Preclinical Development of Hedgehog Inhibitors for the Treatment of Cancer The discovery of the importance of HH signaling in oncogenesis led to the development of HHIs. Most HHIs inhibit HH signaling by binding to Smo (Figure 3) [3], [33]. Currently, 2 HHIs, vismodegib (Genentech Inc, South San Francisco, CA) and sonidegib (Sun Pharmaceutical Industries, Inc, Cranbury, NJ), are approved by the US Food and Drug Administration (FDA) for use in advanced BCC [34], [35]. Itraconazole (Janssen Pharmaceuticals, Inc., Titusville, NJ) [36], an antifungal agent, inhibits HH signaling in cancer and is under investigation for clinical efficacy in several tumor types [37], [38]. Patidegib was granted Orphan Drug and Breakthrough Therapy Designation by the FDA as a topical agent for the treatment of BCCNS [39], [40]. Other HHIs under study for use in cancer are glasdegib and taladegib [41], [42], [43], [44]. A summary of available pharmacokinetic data for HHIs is presented in Table 1. This section provides an overview of the preclinical development of HHIs in various cancers.
    Clinical Evidence for the Efficacy of Hedgehog Inhibitors in Various Cancer Types
    Toxicity Profile Associated with Hedgehog Inhibitor Therapy Patients receiving HHI therapy commonly experience at least 1 treatment-emergent adverse event (AE), including alopecia, muscle spasms, fatigue, vomiting, nausea, and dysgeusia [57], [73], which are thought to be related to HH pathway inhibition in normal tissue [74]. Developmental toxicity was observed in a preclinical mouse model following Smo inhibitor administration [75]. This is consistent with grade 1 and 2 effects on bone and cartilage noted in 3 prepubertal patients treated with sonidegib for medulloblastoma (NCT01125800) ages 4, 8, and 11 years requiring discontinuation [57]. On the other hand, no drug-related bone or dental toxicities were observed in pediatric patients following vismodegib treatment [58]; possibly due to the short treatment duration in the majority of pediatric patients. Of the 4 patients who remained on study with responses to vismodegib, all were postpubertal and above the age of 17 years [57], [58]. These data may limit the utility of targeting this pathway in young children with HH-activated tumors. Otherwise, the low toxicity profile associated with vismodegib and sonidegib treatment in the pediatric population was similar to that observed in adults. Furthermore, no patients withdrew due to unacceptable toxicity [58].