Optimization of dosing regimens of sulindac in combination with erlotinib for small intestine and colorectal cancer prevention
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AbstractIntroduction: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by germline mutations in the APC (Adenomatous polyposis coli) gene. The combination of Sulindac (SUL) with Erlotinib (ERL) for 6 months was effective in reducing duodenal and colon polyp burden in FAP patients. However, toxicity of the two drugs in combination raised concerns about their long- term use in a prevention setting. Current preclinical studies in the polyposis in rat colon (Pirc) model of FAP examined lower and/or less frequent clinically relevant dosing of ERL and SUL.Methods:Pirc males (n=14/group) at 5-6 wks of age were fed AIN93 diet with/without SUL (250 ppm in diet) daily and/or escalating doses of ERL (10, 21, or 42 mg/kg) by oral gavage, once weekly, in a 12-month Chemoprevention Efficacy/Toxicity/Resistance study. In a follow-on 3-month Dose Optimization study, Pirc males (n=10/group) were fed AIN93 diet with/without SUL (250 ppm in diet) and/or lower ERL doses (5 or 10 mg/kg), once or twice weekly. Colon polyps were examined by monthly colonoscopy, and at the end of the study assessed by histology, immunoblotting and RT- qPCR. Colon and small intestine (SI) polyps were recorded for location, multiplicity and volume. Tumors, adjacent normal tissues, and blood samples were collected.Results: Efficacy/Toxicity/Resistance study: Weekly ERL (10, 21, or 42 mg/kg) + daily SUL (250 ppm) demonstrated excellent tumor inhibition (58%, 85.5%, 95.2%, respectively, p>0.001 vs AIN), based on monthly colonoscopy. Treatment inhibited pErk and Wnt pathway genes in colon polyps. Results at necropsy demonstrated dose-dependent tumor inhibition by ERL (10, 21, or 42 mg/kg) + SUL (250 ppm) in the SI (89.1%, 98.8%, 99.3%, p>0.001 vs AIN) and colon (55.2%, 78%, and 95.1%, p>0.001 vs AIN), respectively, consistent with the colonoscopy data. The lowest most efficacious dose was ERL10+SUL (0.24X human loading dose), when compared to tumor inhibition by ERL10 (52.6%, p>0.05 vs ERL10+SUL) or SUL alone (40%, p>0.01 vs ERL10+SUL), indicating synergy, mainly in the SI. Moreover, ERL10+SUL normalized organ weights and hematocrits that were altered in the AIN controls. But, few rats had weight loss, blood in rectum, diarrhea, and skin toxicity. Dose Optimization study: dose and frequency of low-dose SUL and ERL are ongoing, to identify best clinically translatable combinations.Conclusions: These studies have the potential to define new dosing strategies for SUL+ERL that are safe and effective, improving efficacy against colon and SI polyps, while circumventing toxicity and resistance. Outcomes from the current work, and dose optimization in Pirc, should be directly translatable to the clinical management of FAP patients.Acknowledgements: Research supported by NCI Contract Number HHSN261201500018I, Task Order HHSN26100004, and NCI Contract Number 75N91019D00021, Task Order 75N91019F00130.Citation Format: Praveen Rajendran, Ahmetmursel Ulusan, Wan-Mohaiza Dashwood, Sabeeta Kapoor, Altaf Mohammed, Shizuko Sei, Asif Rashid, Powel H. Brown, Eduardo Vilar-Sanchez, Roderick H. Dashwood. Optimization of dosing regimens of sulindac in combination with erlotinib for small intestine and colorectal cancer prevention [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 21.
