Inflammation is a key hallmark of many cancers and potent target for chemoprevention. Experimental and clinical intervention studies indicate strong cancer preventive efficacy of cyclooxygenase (COX)-2 inhibitors. Their use for chemoprevention is limited due to increased cardiovascular (CV) toxicities. Selective COX-2 inhibition diverts arachidonic acid to the 5-lipoxygenase (5-LOX) pathway resulting in accumulation of prothrombotic leukotrienes while depleting antithrombotic prostaglandin (PG)I2, leading to increased risk of CV events. To overcome side effects, balanced dual inhibitors targeting COX-2/5-LOX or microsomal PGE synthase (mPGES)-1/5-LOX enzymes are being developed for chemoprevention. In this study, the clinically advanced dual COX-2/5-LOX inhibitor, licofelone, and its glycine analogue (LFA-9), the mPGES-1/5-LOX dual inhibitor, were evaluated for colon cancer preventive efficacy in the FAP relevant PIRC rat model. In preclinical dose range finding and preliminary toxicity studies in F344 rats, dietary administration of licofelone <500ppm and LFA9 <1,600ppm for 8 weeks showed no signs of toxicity based on by body weight gain, organs histopathology, blood cell counts, and serum chemistry. For efficacy evaluation, male and female PIRC rats were randomized by age (n≥15/group/gender). All rats had pre-intervention colonoscopies (8 weeks age) to determine baseline colonic polyps and were fed AIN-76A diets containing licofelone (250 ppm), LFA-9 (800ppm) or control until 32 (male) or 40 (female) weeks of age. Colonoscopies were repeated every 8 weeks for longitudinal monitoring of tumor development. At the end of the treatment period, rats were euthanized and intestines were evaluated for tumor multiplicity as an efficacy endpoint. Colonoscopy data suggested no significant difference in pretreatment colonic polyp multiplicity. However, there was a marked delay in colon tumor development in rats in the intervention group compared to control. Colonic tumor multiplicity at termination indicated that licofelone treated male rats developed 32% less tumors (21.87±1.23 (Mean±SEM); p<0.0001), while LFA-9 treated male rats had 31% less tumors (22.13±1.19; p<0.0001) compared to controls (32.25±1.37). There was no significant difference in tumor multiplicity between licofelone and LFA-9 treatment groups. In females, licofelone treatment led to 51% inhibition of colonic tumors (9.18±1.25; p<0.0002) while LFA-9 treatment led to 37% inhibition (11.89±0.86; p<0.002) compared to control (18.91±1.88). Although licofelone trended toward better inhibitory effect in females, this was not significantly different from the LFA-9 group. Colon tumor volume and small intestinal tumor multiplicity was notably inhibited in both licofelone and LFA-9 treated rats when compared to control. Our data suggest both licofelone and LFA-9 exhibit moderate and uniform chemopreventive efficacy against FAP-associated intestinal tumorigenesis in the PIRC rat model. (Supported by NCI HHSN HHSN261201500024I)
Citation Format: Venkateshwar Madka, Nagendra S. Yarla, Gopal Pathuri, Yuting Zhang, Anh Bao, Nicole C. Stratton, Anil Singh, David L. McCormick, Altaf Mohammed, Shizuko Sei, Jennifer Fox, Chinthalapally V. Rao. Colon cancer preventive efficacy of licofelone and its analogue LFA-9 in PIRC rat model of FAP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB225.