Significant plasma dose-dependence was observed in flavan-3-ol metabolites of the AGSE group and in Mal, Del and Cyn galactosides and Pet, Peo, and Cyn glucosides of the bilberry groups. In the brain, a significant dose dependence was found in the cerebellum and frontal cortex in all major flavan-3-ol metabolites. All anthocyanidin glycosides, except for delphinidin, showed a dose-dependent increase in the cerebellum.

EC1456, a potent folate-targeted tubulysin conjugate, is currently being evaluated in a phase 1 dose escalation study in patients with advanced solid tumors. To assist in upcoming cancer indication selection decisions for advanced trials, we tested EC1456 against eight patient-derived xenograft (PDX) cancer models. Thus, EC1456 was evaluated as a single agent or in combination with standard of care (SOC) treatments against two folate receptor (FR)-positive models each of ovarian, endometrial, non-small cell lung (NSCLC) and triple negative breast (TNBC) tumor models. Nude mice engrafted subcutaneously with PDX tumors received 4 μmol/kg/week EC1456 for two weeks, following a once a week (SIW) or two times a week (BIW) schedules, either alone or in combination with 15 mg/kg, SIW x 2 Paclitaxel (ovarian and endometrial), 1 mg/kg SIW x 2 eribulin mesylate (TNBC) or 15 mg/kg, SIW docetaxel (NSCLC). EC1456 alone demonstrated tumor growth suppression or stasis in most of the tumor models and significantly greater anti-tumor activity (including cures) with no detectable increase in toxicity when tested in combination with the SOC agents. Overall, EC1456 significantly augmented the growth inhibitory effects of SOC treatments against all four PDX cancer indications examined, thus lending support to future clinical development of this novel FR-targeted agent. Citation Format: Joseph A. Reddy, Alicia Bloomfield, Christina Taylor, Katherine Hargett, Melissa Nelson, Christopher Leamon. Antitumor efficacy of EC1456 in patient derived xenograft models of ovarian, endometrial, NSCLC and TNBC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5359. doi:10.1158/1538-7445.AM2015-5359

To assess the bioavailability and brain accretion of dietary polyphenols, pigs (14 ± .5 lb) were divided into 5 groups (n=8/group) of control (water), low (27.5 mg/kg) or high (82.5 mg/kg) concentration of bilberry extract or apple/grape seed extract (A/GSE). Polyphenol ingredients were delivered once a day. After 3 weeks, a plasma 24h pharmacokinetic study was conducted. Blood and brain regions (stem, cerebellum, cortex, hypothalamus, hippocampus and amygdala) were harvested 24 h later and analyzed for key polyphenol metabolites from (epi)catechin, quercetin and anthocyanins by HPLC‐MS/MS. Polyphenols were not detected in control plasma or brain samples. A significant (p <.05) plasma dose response was observed for epicatechin and catechin metabolites in the A/GSE groups. Most of the plasma anthocyanin metabolites in bilberry groups exhibited significant or trend (0.05 < p < 0.1) dose responses. Brain accumulation varied (in pmol/g tissue): (epi)catechin (7‐1430), quercetin (0.1‐1.2), anthocyanins (0‐3). Significant differences were observed between different brain regions and not all metabolites were detected in all brain regions. The highest concentration for most metabolites was in the cerebellum in both high concentration groups. These data demonstrate that polyphenol metabolites can cross the blood‐brain barrier and accumulate at different concentrations in different brain regions. Grant Funding Source: Supported by Mead Johnson Nutrition