Abstract 16: LTA4 hydrolase inhibitor bestatin prevents intestinal tumors in APC mutant rodent models of FAP

Abstract

Abstract Colorectal cancer (CRC) is the third most common cancer in the United States with 145,600 new cases and 51,020 deaths estimated to occur in 2019. Leukotriene B4 (LTB4), the product of the enzyme leukotriene A4 hydrolase (LTA4H), reportedly plays a role in carcinogenesis. LTA4H over expression and increased LTB4 levels are found in CRC tissues and correlate with both disease stage and reduced survival. Thus, we used a preclinical rodent model to assess repurposing bestatin (Ubenimex), a potent orally-active reversible small molecule inhibitor of LTA4H, for prevention of CRC in high-risk FAP patients. Six week old Apcmin/+ male and female mice (n≥15) were assigned to control and treatment groups; groups received the same diet either with 1000 ppm bestatin (treatment) or no bestatin (control) for 14 weeks at which point mice were euthanized and intestines were evaluated for tumors. Control mice developed colonic tumors with multiplicity of 1.35±0.16 (Mean±SEM) in males and 0.86±0.13 in females. Colonic tumor incidence was 91% and 73% in the male and female mice respectively. Additionally, control mice developed 30.52±1.66 (male) and 29.57±2.74 (female) small intestinal polyps (SIP). Dietary bestatin significantly reduced colon tumor multiplicity. Bestatin treated male mice had 55% fewer colonic tumors (0.60±0.21; p<0.01) and female mice 59% fewer (0.35±0.12; p<0.008) compared to their respective controls. Importantly colonic tumor incidence was inhibited by >50% in both genders. Bestatin administration was reduced colonic tumor incidence by 56% (p<0.001) in male and 52% (p<0.026) in female mice. Small intestinal polyps were also significantly reduced in treated mice compared to controls. Male mice developed 29% less SIP (21.67±2.32; p<0.006) while female had 46% fewer SIP (16.00±1.98; p<0.0005) compared to controls. The polyposis in rat coli (PIRC) model replicates CRC in FAP patients. PIRC rats (n=6) at 8 weeks of age were assessed for polyp number by colonoscopy, and assigned to control and bestatin (1000 ppm) groups for 8 weeks. Colonic polyp inhibition in each rat was evaluated by colonoscopy after treatment. Bestatin treatment led to strong suppression of colonic polyps; significantly fewer (~72% less; p<0.005) colonic polyps were seen in bestatin-treated PIRC rats. Pharmacokinetic analysis demonstrated that dietary bestatin resulted in significant bestatin levels in both serum (15μg/mL) and colonic tissue (up to 250 μg/g). LTB4 levels in both plasma and colon tumors were also significantly lowered by ~70% (p<0.004) and ~26% (p<0.01) respectively. Colonic tumors from the treated animals also showed an increase in NK and NKT cells suggesting immune-modulatory effects of the agent. In summary, bestatin demonstrated excellent safety, pharmacokinetics, and chemopreventive effects against CRC in preclinical models and warrants further validation clinically. Citation Format: Venkateshwar Madka, Gopal Pathuri, Hariprasad Gali, Nandini Kumar, Nagendra Sastri Yarla, Anh Bao, Adam S. Asch, Chinthalapally V. Rao. LTA4 hydrolase inhibitor bestatin prevents intestinal tumors in APC mutant rodent models of FAP [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 16.