Abstract 1681: Paradoxical induction of epithelial hyperplasia by a selective raf inhibitor
Authors: John-Baptiste Annette , Lettiere Daniel J. , Giovanelli Michael A. , Liu Ling , Maier Robyn , Palmer Cindy , Alton Gordon , Yamazaki Shinji , Schmidt Stephen P. , Muravnick Kathleen , Burns-Naas Leigh Ann , Evering Winston , Bagrodia Shubha , Smeal Tod , Torti Vince 
Published: February 2011

Abstract
Raf kinases (A-Raf, B-Raf, C-Raf) link Ras activation to MEK/ERK pathway activation, and are part of the key MAPK signaling pathway that controls cellular functions such as cell proliferation, migration, differentiation, and survival. Activating mutations in B-Raf occurs in a variety of cancers and inhibition of these signaling proteins in the pathway, therefore, represents a therapeutic targeting strategy for diverse cancers.
We developed PF-04880594, an ATP-competitive and reversible inhibitor of B-Raf. To assess safety prior to initiation of clinical trials, repeat dose toxicity studies were performed in the rat and dog. Animals were treated orally at 0, 25, 75, 300→150 mg/kg/day in the rat or 0, 0.5, 6, 15→12 mg/kg/day in the dog for 30 days followed by a 30-day treatment-free period to assess recovery or delayed toxicity. Plasma concentrations of the B-Raf inhibitor were measured on Day 1 and at the end of the dosing phase of the study. Body weight and food consumption were measured at regular intervals and clinical signs were recorded daily. In the rat, dose-related clinical signs, occurring in the skin at ≥ 25 mg/kg included dry skin and/or edema in the paws, erythema and desquamation of tail skin &gt; 75 mg/kg, and erythema of the ear at 300→150 mg/kg. In the dog, clinical signs observed at ≥ 6 mg/kg included desquamation and alopecia of the skin involving the ear, head, eyebrow, muzzle, thorax, lips, nose, scrotum or forepaw; and edema of the ear, muzzle, head, forepaw, hindpaw or scrotum. Erythema was observed at all dose levels on the muzzle, ear or head during life. In both species, these clinical signs correlated microscopically with epithelial hyperplasia in these affected tissues. Hyperplasia of the stratified epithelium of the tongue and esophagus occurred in both species, In the rat, epithelial hyperplasia was additionally observed in the urinary bladder and nonglandular stomach and dose-related proliferation of woven bone was observed primarily on endocortical surfaces in the proximal tibia and /or distal femur. Clinical pathology revealed an inflammatory response indicated by increased fibrinogen and neutrophil counts in dogs at ≥ 6 mg/kg (males &gt; females) and in rats at ≥ 75 mg/kg. At the end of the recovery period, the inflammatory response and the woven bone changes were not evident, but epithelial hyperplasia was only partly resolved. A no-observed-effect-level was not identified in either study due to the epithelial hyperplasia. At low doses, margins of exposure were over 10-fold in the rat and 0.03-fold in the dog of projected clinically efficacious plasma concentration in humans.
These studies indicate epithelial hyperplasia is paradoxically induced by this selective B-Raf inhibitor. The occurrence of this change in the rodent and canine suggests that this effect could develop in other mammalian species. Combination studies to test the effects of Raf and MEK inhibition on hyperplasia are currently being investigated.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1681.