Abstract 1172: In vivo pharmacokinetic properties and antitumor efficacy of porcupine lead inhibitors in the orthotopic murine MMTV-Wnt1 breast tumor model and the human HPAF-II pancreatic xenograft mouse model

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.1172-1172
• Main Authors: Pendharkar, Vishal, Chew, Yun Shan, Manoharan, Vithya, Low, Choon Bing, Ong, Hongqian Esther, Ho, Soo Yei, Wang, Wei Ling, Athisayamani, Jeyaraj Duraiswamy, Madan, Babita, Virshup, David, Keller, Thomas Hugo, Lee, May Ann, Matter, Alex, Hill, Jeffrey, Sangthongpitag, Kanda
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-1172

Porcupine (PORCN), a muti-pass integral membrane-bound-O-Acyl acyltransferase (MBOAT), resides in the in the endoplasmic reticulum (ER) and is required for biogenesis of Wnt ligands. The secreted mature Wnt ligands bind to their cognate receptors (Frizzled, LRP5/6 and transmembrane receptor ROR) to form the ligand - receptor complex which is capable to activate the Wnt-β-catenin signalling cascade and downstream signalling pathways such as mTOR, GSK3, Akt, and PKC. The deregulation of and aberrant activation of the various components of Wnt-β-catenin signalling pathway have been implicated in tumorigenesis, cell proliferation, survival and differentiation. Hyperactivity of PORCN is found to be associated with cancerous cell growth. Knockdown of Porcn mRNA significantly reduced the proliferation of breast cancer cells and resulted in the delay of MDA-MB-231 tumor formation in mouse xenograft models (Covey et al 2012). Loss of function mutations of RNF43, a negative regulation of Wnt-signalling via Frizzled receptor, is recently reported to be involved with pancreatic ductal adenocarcinoma. Inhibition of the PDAC cell lines bearing RNF43 mutations enhanced Wnt-β-catenin signalling and resulted in suppression of proliferation and differentiation of PDAC tumor cells (Jiang et al 2013). Taken together porcupine could be an attractive therapeutic approach for a particular Wnt-driven cancer population. We have identified the porcupine lead compounds (ETC-159, ETC-535, ETC-611 and ETC-539) from different novel chemical scaffolds. The aim of this study was to evaluate their pharmacokinetic properties and antitumor efficacy in different cancer mouse models, the murine MMTV-Wnt1 breast cancer and the human pancreatic HPAF-II cancer. All porcupine lead compounds had good oral pharmacokinetic properties with the absolute oral bioavailability greater than 42%. They had the maximum tolerated dose (MTD-7d) up to 200 mg/kg. They produced antitumor efficacy ranging from 24% to 79% at 1 mg/kg, 38% to 89% at 3 mg/kg, and 58 to 97% at 10 mg/kg in MMTV-Wnt1 tumor mouse model. In vivo inhibition of PORCN led to reduce the expression level of Axin2 in MMTV-Wnt tumors upto 8h. At 100 mg/kg, they produced antitumor efficacy ranging from 34% to 91% in human HPAF-II pancreatic xenograft mouse model. Of 4 porcupine lead compounds, ETC-159 demonstrated great oral pharmacokinetic properties and produced significantly antitumor efficacy (p value < 0.0001) in both cancer mouse models. ETC