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.

Phase II trial of weekly erlotinib dosing to reduce duodenal polyp burden associated with familial adenomatous polyposis

“…A recent study using a murine model of FAP ( APC -mutation polyposis in rat colon, Pirc) suggested that an optimal low dose strategy (using a human equivalent of erlotinib 125 mg one time per week plus daily sulindac) led to significant tumour inhibition in the colon and small intestine while minimising skin toxicity and gastric ulceration. 23 …”

“…Along with the encouraging reductions in duodenal and lower GI polyp burden observed in our study, AEs were frequently A recent study using a murine model of FAP (APC-mutation polyposis in rat colon, Pirc) suggested that an optimal low dose strategy (using a human equivalent of erlotinib 125 mg one time per week plus daily sulindac) led to significant tumour inhibition in the colon and small intestine while minimising skin toxicity and gastric ulceration. 23 To reduce potential bias and interobserver variability, the baseline and 6-month endoscopy were performed by the same endoscopist for all study participants. The endoscopist was not blinded as to whether it was a baseline or endpoint procedure since the placement or existing presence of a tattoo would make it impossible.…”

Metabolomics of Acute vs. Chronic Spinach Intake in an Apc–Mutant Genetic Background: Linoleate and Butanoate Metabolites Targeting HDAC Activity and IFN–γ Signaling

“…Future work should seek to corroborate the concentrations of these metabolites in vivo in the context of apoptosis induction in colon tumors after long-term dietary SPI intake, and phenotypic outcomes following treatment of FAP patient organoids. Clinical translation of freeze-dried whole foods, such as SPI, to at-risk patients might provide valuable quality-of-life benefits via inflammasome/immune mechanisms, delaying colectomy and drug intervention [44][45][46][47][48][49][50].…”

How many is too many? Polyposis syndromes and what to do next

“…Those with an end ileostomy should have surveillance every 2 years [17]. The role of chemoprevention in management of FAP is actively being studied [18] with promising results for sulindac and erlotinib [19,20,21].…”