The Hedgehog Signaling Pathway

The Hedgehog Signaling Pathway

The discovery of postnatal activation of the fundamental developmental Hedgehog (Hh) signaling pathway in a number of human cancers has opened a new field for pharmaceutical intervention and modulation. Several Hh pathway antagonists have been developed and evaluated in phase I and II clinical trials, and at least two have been approved for use by the U.S. Food and Drug Administration (FDA).

The association between activated Hh pathway and cancer was first defined in patients with basal cell nevus syndrome (BCNS, or Gorlin syndrome)—an autosomal-dominant disorder with mutations in the PTCH1 gene. These patients have an increased incidence of basal cell carcinoma (BCC), medulloblastoma, and other malignancies. It has also been proposed that the Hh pathway contributes to the growth of a variety of tumors of endodermal origin, including breast, esophageal, pancreatic, lung, colon, and prostate cancers. Aberrant Hh pathway activation has also been implicated in hematologic malignancies, including multiple myeloma, chronic myelogenous leukemia, and B-cell acute lymphocytic leukemia.

Fig. 1.
Figure 1 shows a simplified schematic of the Hh signaling pathway. In the absence of Hh ligand, a cell-surface transmembrane protein called patched (PTCH) inhibits the activity of a seven-transmembrane protein, smoothened (SMO). Inactivation of PTCH by binding with Hh permits the activation of SMO. This subsequently activates transcription factors that enable the transcription of genes in the pathway, including PTCH and GL1.

A more detailed description of the Hh signaling pathway was presented in an original article by James Kim, MD, PhD, and Charles M. Rudin, MD, PhD, in the ASCO Daily News, on which this fact sheet is based.

Hh Pathway Antagonists

Cyclopamine and jervine were the first inhibitors identified as Hh pathway antagonists. Cyclopamine was later shown to bind directly to and trap SMO in its inactive form. All Hh pathway antagonists under commercial development inhibit SMO by binding to a region that overlaps the cyclopamine-binding site.

The FDA has approved two drugs in this class: vismodegib and sonidegib.1,2 Other drugs in development include BMS-833923, glasdegib (PF-04449913), and taladegib (LY2940680). Similar SMO inhibitors saridegib and TAK-441 are no longer in development.

The antifungal agents itraconazole and arsenic trioxide have been shown to be Hh pathway inhibitors. Itraconazole inhibits SMO at a distinct site from cyclopamine and other SMO antagonists and has been evaluated in clinical trials. Arsenic trioxide inhibits the GLI transcription factors through their destabilization or enhancement of degradation.

Other strategies to inhibit the Hh pathway are in research phases only. They include Hh ligand antagonists, inhibitors of Hh ligand palmitoylation, GLI antagonists, microtubule inhibitors, primary cilia inhibitors, and inhibition of SMO localization in primary cilia.

The following are some of the notable clinical trials exploring Hh pathway inhibition.

Basal Cell Carcinoma

The most common cancer in the United States, BCC was the first tumor to be treated with SMO antagonists and has served as the model tumor for Hh pathway inhibition.3 Most BCCs, including both sporadic and Gorlin syndrome, are driven by ligand-independent Hh pathway activation. PTCH1 mutations and activating SMO mutations are found in approximately 90% and 10% of BCC, respectively. Prior to the SMO antagonists, few options were available for locally advanced and metastatic disease.

A phase I study reported the first use of the Hh pathway antagonist vismodegib in humans.3 Of 33 patients with locally advanced or metastatic BCC treated with vismodegib, two patients had complete response (CR), 16 patients had partial response (PR), 11 patients had stable disease, and four patients had progressive disease.

The multicenter, phase II, open-label ERIVANCE trial enrolled 33 patients with metastatic BCC and 63 with locally advanced unresectable BCC. Patients with metastatic BCC had a 30% response rate, and patients with locally advanced disease had a 43% response rate, with a 21% CR rate. In an 18-month update, overall response rates (ORRs) of 60.3% and 48.5% were reported for patients with locally advanced and metastatic disease, respectively.4 Patients with metastatic BCC had a median overall survival (OS) of 30.9 months. In an update 12 months after the primary analysis, the ORR of patients with locally advanced disease and of patients with metastatic disease increased to 48% and 33%, respectively, and median duration of response of patients with locally advanced disease increased from 7.6 to 9.5 months.5

A randomized, placebo-controlled, phase II trial of 41 patients with BCNS treated with 150 mg of vismodegib per day showed that new BCC formation decreased to two per year, compared with 29 per year with placebo. Vismodegib treatment also decreased the mean size of existing tumors by 65%, compared with 21% for placebo.6

Based on these studies, the FDA approved vismodegib in 2012 for the treatment of unresectable, locally advanced, and metastatic BCC.1

An interim analysis of the STEVIE multicenter, open-label trial assessed the safety and efficacy of vismodegib in 499 patients with locally advanced or metastatic BCC.7 Muscle spasms, alopecia, dysgeusia, weight loss, and asthenia were the most common toxicities. Thirty-six percent of patients withdrew because of adverse effects, with 22% of patients experiencing serious adverse events. ORR was 55%, with 32% CR (mostly among patients with locally advanced disease), 33% PR, and 27% stable disease.

Sonidegib was evaluated in a multicenter, double-blind, randomized, two-arm, noncomparative trial in 230 patients with locally advanced BCC not amenable to local therapy or with metastatic BCC.8 Patients were randomly assigned to 2:1 to sonidegib 800 mg or 200 mg daily until disease progression or unacceptable toxicity. Randomization was stratified by disease stage (locally advanced or metastatic) and other factors. Most (84%) of those enrolled had locally advanced disease. ORR—the principal efficacy outcome—for 42 patients with locally advanced BCC was 43% and 35% for the sonidegib 200-mg and 800-mg arms, respectively. For patients with metastatic disease, ORR was 15% for the 200-mg arm and 17% for the 800-mg arm. The most common toxicities were similar to those reported for vismodegib, except for increased blood creatine kinase, which was the most common grade 3/4 adverse event.

Based on these results, the FDA approved sonidegib in July 2015 for treatment of patients with locally advanced BCC that has recurred following surgery or radiation therapy and for those who are not candidates for surgery or radiation therapy.2

Itraconazole was used as an Hh pathway antagonist for patients with BCC in a pilot biomarker-driven, open-label, phase II clinical trial. In 19 patients with multiple BCCs, 24% experienced a decrease in tumor area, 65% had a reduction in Hh pathway activity, and 45% had a reduction in cell proliferation marker Ki-67.9


Medulloblastoma is the most common pediatric primary central nervous malignancy, accounting for approximately 20% of childhood brain tumors.

Vismodegib was evaluated in two phase II trials in pediatric (PBTC-032) and adult (PBTC-025B) patients with medulloblastoma.10 Vismodegib exhibited activity against recurrent medulloblastoma only in the sonic hedgehog (SHH) subgroup but not against recurrent non-SHH medulloblastoma. Three adult patients and one pediatric patient experienced sustained responses. Progression-free survival (PFS) was longer in adult patients with SHH-positive medulloblastoma, compared with SHH-negative medulloblastoma. Because of poor accrual in the pediatric population, efficacy of vismodegib could not be concluded. Median ratio of cerebrospinal fluid vismodegib to unbound plasma vismodegib was 0.53.

A phase I/II study of recurrent pediatric medulloblastomas and solid tumors treated with sonidegib reported CR in two of 24 patients with medulloblastoma. These two patients were in the SHH subgroup, whereas the other 22 patients with medulloblastoma were not.11

Pancreatic Cancer

SHH is overexpressed in more than 70% of pancreatic cancers.12 At least two phase II trials in pancreatic cancer using an SMO inhibitor and gemcitabine have been completed.

A randomized, double-blind, placebo-controlled trial comparing saridegib and gemcitabine with placebo and gemcitabine showed a worse median survival for the saridegib arm (< 6 months) compared with the control arm (> 6 months) because of a higher rate of progressive disease during an interim analysis. The trial was discontinued after these results.13

A phase Ib/II randomized, placebo-controlled trial comparing vismodegib and gemcitabine with placebo and gemcitabine showed no improvement in PFS or OS compared with gemcitabine alone.12

Other clinical trials of SMO inhibitors in pancreatic cancer were ongoing at the time of this report.

Small Cell Lung Cancer

Based on promising preclinical studies in models of small cell lung cancer, a three-arm, randomized, phase II clinical trial (ECOG-1508) assessed vismodegib in combination with cisplatin/etoposide chemotherapy (CE), cixutumumab (an inhibitor of IGF-1R) plus CE, and CE alone in patients with extensive-stage small cell lung cancer. The study accrued more than 50 patients to each arm. No improvement in PFS was seen in either of the two investigational arms compared with CE alone.14

Other Solid Tumors

Trials in gastric cancer, colon cancer, and chondrosarcoma have not shown significant improvement in PFS or OS with the use of an SMO antagonist.

Future Directions

As these clinical trials show, the range of patients who might benefit from Hh pathway antagonists is unclear. Perhaps only those tumors driven by mutations in the pathway that spur tumor growth, such as BCC and medulloblastoma, will be responsive to pathway antagonists. In that sense, these results mirror the experience with other targeted agents.

If Hh pathway antagonists are to have a role in the treatment of non-BCNS–type tumors, patient selection will be a key factor for future trials. Unfortunately, reliable biomarkers that are surrogates of pathway activity and predictors of response to SMO antagonists are lacking. The dearth of reliable commercially available antibodies against key Hh pathway components limits the use of standard immunohistochemistry to test for pathway activity in clinical samples.

Attempts to develop biomarkers are being made. A five-gene real-time polymerase chain reaction Hh signature has been developed from previous microarray analyses of 25 SHH-group medulloblastoma samples from patients treated with sonidegib. A test of the signature was performed retrospectively on 50 medulloblastoma samples treated with sonidegib from three phase I clinical trials. Nine patients were identified as Hh-pathway positive, with six patients achieving PR or CR, one patient with stable disease, and two patients with progression after 36 and 65 days of therapy.15

A four-antibody immunohistochemical panel to segregate tumors into Wnt, SHH, and non-Wnt/non-SHH subgroups (NCT01878617) is being used in a clinical and risk-directed therapeutic clinical trial.16 No results of this trial have been published. However, even if these biomarker methods are validated for medulloblastoma in larger studies, they may be tumor- and tissue-specific. Further testing will be required before these methods can be generalized to other tumors.

Another concern is that the clinical trials in sporadic epithelial tumors have used standard cytotoxic chemotherapy in combination with an SMO inhibitor. It may be that, as seen with tyrosine-kinase inhibitors, Hh pathway antagonists have a similar role in combination with chemotherapy, and concurrent use of pathway antagonists and chemotherapy may be counterproductive. An alternative strategy may be to use combinations of other targeted agents with Hh pathway antagonists.  

–Tim Donald, ELS