HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Drug Saf Manuscript Author . Author manuscript; Manuscript Author available in PMC 2020 February 01. Published in final edited form as: Drug Saf. 2019 February ; 42(2): 263–279. doi:10.1007/s40264-018-0777-5. Efficacy and safety of sonic hedgehog pathway inhibitors in cancer Richard L Carpenter1,2,3,* and Haimanti Ray2 1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 1001 E. 3rd St, Bloomington, IN 47405 2Medical Sciences, Indiana University School of Medicine, 1001 E. 3rd St, Bloomington, IN 47405 3Simon Cancer Center, Indiana University School of Medicine, 1001 E. 3rd St, Bloomington, IN 47405 Abstract The hedgehog pathway, for which sonic hedgehog (Shh) is the most prominent ligand, is highly conserved and is tightly associated with embryonic development in a number of species. This pathway is also tightly associated with development of several types of cancer, including basal cell carcinoma and acute promyelocytic leukemia (APL) among many others. Inactivating mutations in Patched 1 (PTCH1), leading to ligand-independent pathway activation, are frequent in several cancer types but most prominent in basal cell carcinoma. This has led to the development of several compounds targeting this pathway as a cancer therapeutic. These compounds target the inducers of this pathway in Smoothened (SMO) and the GLI transcription factors, although targeting SMO has had the most success. Despite the many attempts at targeting this pathway, there are only three FDA-approved drugs for cancers that affect the Shh pathway. Two of these compounds, vismodegib and sonidegib, target SMO to suppress signaling from either PTCH1 or SMO mutations that lead to upregulation of the pathway. The other approved compound is arsenic trioxide (ATO), which can suppress this pathway at the level of the GLI proteins, although current evidence suggests it also has other targets. This review focuses on the efficacy and safety of these clinically-approved drugs targeting the Shh pathway along with a discussion on other Shh pathway inhibitors being developed. 1. Introduction The hedgehog pathway is a highly conserved signaling pathway that is linked to many biological processes. This signaling pathway has been linked to development in many species, including humans (1). It has been linked to growth and patterning in many of these multicellular species including the development of the neural system and bone development (2, 3). The hedgehog pathway and its components have also been linked to several diseases, prominently including human cancer (4). Because of the importance of this pathway to human cancer, there have been several attempts to target this pathway for cancer therapies *Corresponding Author: [email protected]; Phone: (812) 855-8214. Conflict of Interest: Richard L Carpenter and Haimanti Ray have no conflicts of interests to declare. Carpenter and Ray Page 2 with few successes and many failures. In this review, we aim to provide an update on the Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author successful agents targeting the hedgehog pathway that have been FDA approved for treatment in human cancers. We will also briefly discuss agents that are currently being developed to target this pathway for the treatment of cancer. 2. The Hedgehog Pathway in Cancer Mammalian hedgehog signaling can be initiated by three unique ligands in Sonic Hedgehog (Shh), Indian hedgehog, and Desert hedgehog. However, Shh is the most widely expressed and also the most potent of these ligands (1, 5). The ligand Shh is expressed as an inactive full-length protein that is proteolytically cleaved to two proteins and the N-terminal 19 kDa fragment is the active Shh ligand (6). The receptor for this active Shh ligand is Patched1 (PTCH1), a 12-transmembrane protein that binds Shh ligand. Binding of Shh to PTCH1 relieves repression of Smoothed (SMO) by PTCH1 thereby activating SMO signaling activity (Figure 1). The activation of SMO ultimately decreases the interaction between suppressor of fused homolog (SUFU) and GLI proteins that allows GLI proteins to enter the nucleus and bind transcriptional targets to regulate cellular gene expression. There are three GLI isoforms in mammals in GLI1-3 wherein gene expression can be induced by GLI1 and repressed by GLI3 whereas GLI2 can regulate expression in either direction. The GLI proteins are the terminal effectors of the Shh signaling pathway and regulate genes that control organismal patterning and development. Many of the genes regulated by GLI proteins are co-opted by cancer cells as they regulate several cancer-related processes including proliferation, migration and invasion, as well as neovascularization (4). There have been numerous reports of genetic alterations in key components of the Shh pathway in different tumor types that leads to constitutive signaling of this pathway and that paracrine signaling of Shh may be an important factor in multiple tumor types (7, 8). While there are reports of the Shh pathway being modified in several tumor types such as breast, pancreatic, colorectal, and rhabdomyosarcoma among several, genetic alterations in this pathway are most consistently seen in basal cell carcinomas (BCCs) and medulloblastomas (9–19). The genetic alterations in this pathway are commonly loss-of-function changes to suppressors of the pathway (e.g. PTCH1, SUFU) or gain-of-function changes to promotors of the pathway (e.g. SMO, GLI). This is very prevalent in BCC as PTCH1 has a gene inactivating alteration in 73% of these tumors while SMO has a genetic activation in 20% (20). Therapies targeted to the Shh pathway primarily inhibit the components that promote signaling flux through the pathway including Shh ligand itself, SMO, and GLI proteins. The most successful strategy has been to target SMO with small molecule compounds and the two FDA-approved drugs targeting this pathway use this strategy. Targeting SMO in BCC, for instance, has the potential to target the large percentage of these tumors that harbor inactivating alterations to PTCH1 or activating mutations to SMO. There are also inactivating alterations to SUFU in 8% of BCCs (20) and GLI1 is amplified in several tumor types (4) but SMO inhibitors are unlikely to show efficacy against these populations. There have been attempts to develop inhibitors to Shh and GLI1 but these have yet to make it past clinical trials. Drug Saf. Author manuscript; available in PMC 2020 February 01. Carpenter and Ray Page 3 Author ManuscriptAuthor 3. Manuscript Author Currently Manuscript Author Approved Shh Manuscript Author Pathway Inhibitors The first FDA-approved drug for cancer that targeted the Shh pathway was arsenic trioxide (ATO) in 2000, which was approved for treatment of acute promyelocytic leukemia (APL) (21). While it has been proven to have significant effects suppressing the Shh pathway, it likely also targets other mechanisms promoting APL development and progression. Despite, ATO being the first FDA-approved drug that does have effects on the Shh pathway, the first FDA-approved agent that was specifically designed to target the Shh pathway was vismodegib (GDC-449), which was originally discovered in 2009 and later approved for treatment of basal cell carcinoma in 2012 (22, 23). A year later in 2010, sonidegib (LDE225) was discovered and was later also approved for treatment of basal cell carcinoma in 2015 (24, 25). These are currently the only approved agents targeting the Shh pathway with indications for cancer (Table 1). 3.1. Arsenic Trioxide (ATO) Arsenic formulations have been used for their beneficial therapeutic effects as far back as the 17th century (21). However, chronic exposure to arsenic is also labeled as a carcinogen and has been shown to promote solid tumors (26, 27). As an anti-cancer therapeutic, ATO has been shown to suppress growth in preclinical models in many tumor types including breast cancer, pancreatic cancer, colon cancer, acute promyelocytic leukemia (APL), melanomas, glioblastoma, and medulloblastoma among others (28–32). Arsenic trioxide (ATO) was initially approved as a therapy for patients with acute promyelocytic leukemia (APL) who are refractory or have relapsed on retinoid and anthracycline chemotherapy (21). This approval came after two landmark trials wherein APL patients had become resistant to standard therapies of chemotherapy or all-trans retinoic acid (ATRA) (33, 34). ATO treatment increased the complete response rate from <40% to >90% and extended the time of this complete response (33, 34). ATO has since been approved for patients with low- and intermediate-risk APL by the EU and approved by the US FDA in combination with ATRA for newly-diagnosed low-risk APL with the t(15; 17) translocation of PML-RARA. ATO has been investigated in several other tumor types, including those with increased Shh dependence, but APL is currently the only indication approved for ATO. 3.1.1. Mechanism of action: APL develops in 95% of cases due to fusion of the promyelocytic gene (PML) on chromosome 15 with the retinoic acid receptor alpha gene (RARA) on chromosome 17 resulting in the PML-RARA t(15; 17) fusion protein (35). The PML-RARA fusion protein acts a transcriptional repressor to block myeloid differentiation. Early studies indicated ATO was effective against PML as exposure to ATO led to decreased levels of PML-RARA protein, as well as other cell survival proteins, and differentiation (29, 36–38). These results led to studies that found significant clinical benefit for APL patients receiving ATO and eventual FDA approval (37, 39). Despite this obvious link of ATO affecting the precise mechanism leading to APL, recent studies have also indicated that ATO has an effect in suppressing the Shh pathway. One of these early findings indicated that ATO suppressed GLI transcriptional activity that was not linked to cell viability, suggesting ATO Drug Saf. Author manuscript; available in PMC 2020 February 01. Carpenter and Ray Page 4 was specifically targeting the Shh pathway (40).