First-in-human phase 1 study of ETC-159 an oral PORCN inhbitor in patients with advanced solid tumours.

Abstract

2584 Background: The Wnt signalling pathway is involved in cellular proliferation, differentiation, migration and implicated in stem cell function in several cancers. ETC-159 is a selective small molecule inhibitor of porcupine, an enzyme required for palmitoylation and secretion of all Wnt ligands. In preclinical studies, ETC-159 induced tumour regression in patient-derived xenograft models. Methods: Open-label, multi-centre study to determine safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics (PD) of ETC-159 given orally, once every other day in a 28d cycle. PD was evaluated by AXIN2 mRNA levels in whole blood and hair follicles and bone turnover by radiological and serum markers. Dose escalation was by ordinal continual reassessment method with a dose-limiting toxicity (DLT) period of 28d. Results: As of 18 Jan 2017, 16 patients (pts) were treated in 6 cohorts at 1 mg (2pts), 2 mg (2pts), 4 mg (3pts), 8 mg (4pts); 16 mg (3pts), and 30 mg (2pts). 80% were male, median age (range) was 55yr (19-68). One DLT was seen at 16 mg due to hyperbilirubinaemia. Adverse events (≥ 20%) were vomiting (32%); anorexia and fatigue (31%); dysgeusia and constipation (25%). ETC-159 Cmax increased with dose with a mean t1/2 of 14 hr. Plasma levels of ETC-159 that inhibited colony formation in vitro were attained from 4 mg onwards. Reduction of whole blood and hair follicle AXIN2 mRNA levels and doubling of serum β-CTX levels was first observed at 4 mg and at C1D15 in some patients. PD modulation increased with dose, consistent with on-target modulation of Wnt signalling. Two pts had β-CTX rise > 1000 pg/mL (reference limit) and a ≥ 5% reduction in bone density by C3D1. Both took vitamin D and calcium supplements and were given i.v. bisphosphonates. No responses were seen but 2 pts (2 mg: colorectal and 4 mg: peritoneal carcinoma) had stable disease for 6 and 8 cycles respectively. Dose-escalation is ongoing at 30 mg. Conclusions: ETC-159 inhibits Wnt signalling at doses that are well tolerated. β-CTX levels increased early on, and in two pts were associated with reduced bone mineral density. Early and regular monitoring of bone turnover is indicated. This study was sponsored by D3 which is funded by NMRC, NRF and BMRC Singapore. Clinical trial information: NCT02521844.

PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers

“…It was also reported that long-term exposure to a PORCN inhibitor in vitro selected for a AXIN1-mutant clone in a RSPO3-translocated colorectal cancer cell line and the AXIN1 mutation drove acquired resistance to the PORCN inhibitor [20]. Moreover, on-target adverse effects of Wnt pathway blockade by PORCN inhibitors, including bone loss and dysgeusia, were observed in a preclinical study and clinical trials [21][22][23]. One strategy to overcome drug resistance and reduce adverse effects is synergistic drug combinations, through which lower drug doses can be used to achieve improved anticancer efficacy.…”

Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche

“…For example, we and others found that daily oral doses of PORCN inhibitors that gave 95% tumor growth inhibition in mouse xenograft models produced no discernable effect on the intestinal epithelium (Madan et al, 2016;Proffitt et al, 2013;Liu et al, 2013). Moreover, the PORCN inhibitor ETC-159 is also well tolerated in humans in phase I clinical trials (Teneggi et al, 2016;Ng et al, 2017). As recent studies indicate that subepithelial myofibroblasts, rather than the intestinal epithelium, are an important source of Wnts and Wnt agonists in the gut essential for intestinal homeostasis (Kabiri et al, 2014;Greicius et al, 2018), here we tested if these myofibroblasts, and more broadly, intestinal stromal cells, are intrinsically drug resistant.…”

The Myofibroblasts’ War on Drugs

“…The authors start by investigating a surprising discrepancy: shutting down Wnt ligand secretion through PORCN inhibition or genetic knockout in purely epithelial ''mini-guts'' (organoids) leads to complete disruption of the stem cell niche. In striking contrast, mice treated with comparable doses of PORCN inhibitors display negligible gut toxicity (Madan et al, 2016), and an early-stage clinical trial corroborates these findings in hu-mans (Ng et al, 2017). The authors propose that the explanation for this is found in the myofibroblasts, as the sensitivity of epithelial organoids to PORCN inhibition was reduced when they were co-cultured with myofibroblasts.…”