TY - JOUR
T1 - Optimization of erlotinib plus sulindac dosing regimens for intestinal cancer prevention in an APC-mutant model of familial adenomatous polyposis (FAP)
AU - Ulusan, Ahmet M.
AU - Rajendran, Praveen
AU - Dashwood, Wan Mohaiza
AU - Yavuz, Omer F.
AU - Kapoor, Sabeeta
AU - Gustafson, Trace A.
AU - Savage, Michelle I.
AU - Brown, Powel H.
AU - Sei, Shizuko
AU - Mohammed, Altaf
AU - Vilar, Eduardo
AU - Dashwood, Roderick H.
N1 - Funding Information:
This research was supported by Contract No. HHSN261201500018I, Task Order HHSN26100004, from the NCI PREVENT Program. R.H. Dashwood was also supported by grants CA090890 and CA122959 from the NCI, by the John S. Dunn Foundation, by AgriLife Research, and by a Chancellor’s Research Initiative from Texas A&M University. Funding was also provided by grant P30 CA016672 (US NIH/NCI) to the University
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
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U2 - 10.1158/1940-6207.CAPR-20-0262
DO - 10.1158/1940-6207.CAPR-20-0262
M3 - Article
C2 - 33277315
AN - SCOPUS:85102113139
SN - 1940-6207
VL - 14
SP - 325
EP - 336
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 3
ER -