Optimization of Erlotinib Plus Sulindac Dosing Regimens for Intestinal Cancer Prevention in an Apc-Mutant Model of Familial Adenomatous Polyposis (FAP).

Abstract

A clinical trial in patients with familial adenomatous polyposis (FAP) demonstrated that sulindac plus erlotinib (SUL+ERL) had good efficacy in the duodenum and colon, but toxicity issues raised concerns for long-term prevention. We performed a biomarker study in the polyposis in rat colon (Pirc) model, observing phosphorylated Erk inhibition in colon polyps for up to 10 days after discontinuing ERL+SUL administration. In a follow-up study lasting 16 weeks, significant reduction of colon and small intestine (SI) tumor burden was detected, especially in rats given 250 ppm SUL in the diet plus once-a-week intragastric dosing of ERL at 21 or 42 mg/kg body weight (BW). A long-term study further demonstrated antitumor efficacy in the colon and SI at 52 weeks, when 250 ppm SUL was combined with once-a-week intragastric administration of ERL at 10, 21, or 42 mg/kg BW. Tumor-associated matrix metalloproteinase-7 (Mmp7), tumor necrosis factor (Tnf), and early growth response 1 (Egr1) were decreased at 16 weeks by ERL+SUL, and this was sustained in the long-term study for Mmp7 and Tnf. Based on the collective results, the optimal dose combination of ERL 10 mg/kg BW plus 250 ppm SUL lacked toxicity, inhibited molecular biomarkers, and exhibited effective antitumor activity. We conclude that switching from continuous to once-per-week ERL, given at one-quarter of the current therapeutic dose, will exert good efficacy with standard-of-care SUL against adenomatous polyps in the colon and SI, with clinical relevance for patients with FAP before or after colectomy. PREVENTION RELEVANCE: This investigation concludes that switching from continuous to once-per-week erlotinib, given at one-quarter of the current therapeutic dose, will exert good efficacy with standard-of-care sulindac against adenomatous polyps in the colon and small intestine, with clinical relevance for patients with FAP before or after colectomy.

• Authors: Ahmet M Ulusan, Praveen Rajendran, Wan Mohaiza Dashwood, Omer F Yavuz, Sabeeta Kapoor, Trace A Gustafson, Michelle I Savage, Powel H Brown, Shizuko Sei, Altaf Mohammed, Eduardo Vilar, Roderick H Dashwood
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 14 Issue 3 Pg. 325-336 (03 2021) ISSN: 1940-6215 [Electronic] United States
• PMID: 33277315 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Sulindac
• Erlotinib Hydrochloride

Topics

• Adenomatous Polyposis Coli (drug therapy, genetics, metabolism, pathology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, standards)
• Colonic Neoplasms (genetics, metabolism, pathology, prevention & control)
• Colonic Polyps (genetics, metabolism, pathology, prevention & control)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Erlotinib Hydrochloride (administration & dosage)
• Genes, APC
• Intestinal Neoplasms (genetics, metabolism, pathology, prevention & control)
• Male
• Mutation
• Rats
• Sulindac (administration & dosage)