Journal
CANCER PREVENTION RESEARCH
Volume 14, Issue 3, Pages 325-336Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1940-6207.CAPR-20-0262
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Funding
- NCI PREVENT Program [HHSN261201500018I, HHSN26100004]
- NCI [CA090890, CA122959]
- John S. Dunn Foundation
- AgriLife Research
- Chancellor's Research Initiative from Texas AM University
- US NIH/NCI [P30 CA016672]
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The study suggests that switching erlotinib from continuous to once-a-week dosing at one-quarter of the standard dose, combined with sulindac, effectively inhibits adenomatous polyps in the colon and small intestine, with clinical significance for patients with FAP.
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 SUI, was combined with once-a-week intragastric administration of ERI, at 10, 21, or 42 mg/kg BW. Tumor-associated matrix rnetalloproteinase-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 Mmp7and 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.
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