Optimizing erlotinib plus sulindac dosing regimens in a preclinical model of FAP
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AbstractIntroduction Colorectal cancer (CRC) involves sporadic cases and hereditary syndromes, such as familial adenomatous polyposis (FAP). In FAP patients, surgical intervention often is coupled to prevention strategies using nonsteroidal anti-inflammatory drugs. However, none of the current therapeutic options is fully effective. A recent trial in FAP patients combined standard of care Sulindac (SUL) treatment with daily Tarceva/erlotinib (ERL), and had good efficacy in reducing adenomatous polyp burden. Toxicity concerns, however, raised questions over the combination strategy for long-term prevention (Samadder et al. 2016). Using the Apc-mutant polyposis in rat colon (Pirc) model as a mimic of human FAP, we sought to optimize the dosing regimens for SUL+ERL for an improved safety profile, while retaining efficacy in the GI tract.Methods In a short-term pharmacodynamic biomarker study, rats (n=7) were fed AIN control diet or AIN diet containing 250 ppm SUL, either alone or in combination with ERL, given by oral gavage at 6 or 12 mg/kg (daily), 21 mg/kg (twice weekly), or 42 mg/kg (once weekly). Colon and small intestine (SI) polyps were resected at 0.5, 1, 2, 3, 7, 10, and 14 days after dosing, and assessed by immunoblotting (IB) or RT-qPCR for changes in pErk/Erk, pAkt/Akt, and other biomarkers. In a follow-up efficacy study, rats (n=10) were given SUL, ERL, or ERL+SUL using dosing regimens that were dictated by recovery times for pErk in the biomarker study. Colon and SI polyps were recorded at necropsy for location, incidence, multiplicity, and volume. Tumors and adjacent normal tissues were taken for histopathology and molecular analyses.Results The biomarker study revealed that pErk was inhibited in Pirc colon polyps for up to 10 days after discontinuing ERL treatment, with full recovery on or around day 14. Nuclear -catenin, c-Myc, Mmp-7 and Cyclin D1 also were attenuated by ERL+SUL in colon polyps. In the efficacy study, results accrued via endoscopy at 3, 4 and 5 months were remarkably consistent with data obtained during final necropsy, at 6 months. Compared to AIN controls, multiple ERL+SUL groups exhibited significant suppression of polyps in the colon (78-98% inhibition, p>0.001) and SI (91-100% inhibition, p>0.001). Molecular analyses revealed that pErk was inhibited in adenomatous polyps, along with downregulation of -catenin targets (c-Myc, Mmp-7). No overt toxicity was detected, other than mild skin changes in groups given ERL.Conclusions These studies have the potential to define safe and effective dosing strategies for SUL+ERL, improving efficacy against colon and SI polyps, while circumventing toxicity and resistance. Outcomes from the current work, plus an ongoing one-year toxicity/resistance trial in Pirc, should be directly translatable to the clinical management of FAP patients exhibiting similar pathology and phenotype. Supported by NCI Contract Number HHSN261201500018I, Task Order HHSN26100004.Citation Format: Ahmetmursel Ulusan, Praveen Rajendran, Wan-Mohaiza Dashwood, Altaf Mohammed, Shizuko Sei, Powel H. Brown, Eduardo Vilar-Sanchez, Roderick H. Dashwood. Optimizing erlotinib plus sulindac dosing regimens in a preclinical model of FAP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5074.
