Abstract 5276: Immunomodulatory activity of intermittent low-dose erlotinib plus sulindac: Implications for hereditary and sporadic colorectal cancer
Authors: Tripathi Chakrapani , Perez Jorge E. Tovar , Kapoor Sabeeta , Muhsin Ahmed , Dashwood Wan Mohaiza , Demirhan Yunus , Demirhan Melek , Shapiro Alessandro , Mohammed Altaf , Sei Shizuko , Brown Powel H. , Savage Michelle I. , Vilar Eduardo , Rajendran Praveen , Dashwood Roderick H. 
Published: March 2024

Abstract
A once-weekly optimized dosing regimen of erlotinib (ERL) in the polyposis in rat colon (Pirc) model [1] was a reliable predictor of antitumor efficacy in familial adenomatous polyposis (FAP) patients [2]. Pirc rats are increasingly used as a translational tool for FAP studies. Based on transcriptomic data from FAP patients receiving ERL plus sulindac (SUL) vs. placebo [3], we determined the timing of changes in interferon-γ signaling in Pirc adenomas, while performing additional dose titration. In rats that were given ERL administered at 5 mg per kilogram of body weight through oral gavage (two times a week) and that received a diet containing 125 parts per million of SUL, a regimen referred to as SUL125+ERL5x2, significant suppression of tumor growth was observed. This combination represented half of the standard of care SUL dose and about one-quarter of the ERL dose in FAP patients. In adenomas collected after one year of treatment from SUL125+ERL5x2 treated rats, the expression of genes related to the major histocompatibility complex (MHC) class I (β2m, Cnx, Psmb8 and Tap1) and MHC class II (RT1-A2, Cd74, RT-1Bb, Cd74, and Ciita) was increased, compared to vehicle controls, excluding a subset of adenomas that remained resistant. Through the use of multiplex mass cytometry (CyTOF), an increase in tumor-infiltrating CD4+ T cells was observed in adenomas from the SUL125+ERL5x2 treatment group. Administration of single or combined agents increased CD68+ cells and reduced the presence of Foxp3+ and Arg1+ cells in Pirc adenomas. The natural history of adenomatous colon polyps indicated an increase in MHC gene expression as tumors increased in size; however, this trend reversed markedly in fully occluding lesions. Additionally, expression of MHC-related factors increased in Pirc colon adenoma and murine colon carcinoma cells treated with ERL±SUL, resulting in enhanced CD8+ T-cell activation and IL-2 secretion. In conclusion, treatment with intermittent low doses of ERL±SUL increased MHC gene expression and induced changes in the immune cell component in the tumor microenvironment of Pirc rat adenomas. A subset of non-responsive adenomas could benefit from additional immunopreventive approaches, with implications for possible clinical applications in both hereditary and sporadic colorectal cancer.
References:1.- Ulusan AM et al., Cancer Prev Res (Phila) 2021;14(3):325-336. 2. Samadder NJ et al., Gut. 2023;72(2):256-263. 3.- Delker DA et al., Cancer Prev Res (Phila). 2018;11(1):4-15.
Funding: This work was supported by the NCI Prevent Program 75N91019D00021, Task Order 75N91019F00130
Citation Format: Chakrapani Tripathi, Jorge E. Tovar Perez, Sabeeta Kapoor, Ahmed Muhsin, Wan Mohaiza Dashwood, Yunus Demirhan, Melek Demirhan, Alessandro Shapiro, Altaf Mohammed, Shizuko Sei, Powel H. Brown, Michelle I. Savage, Eduardo Vilar, Praveen Rajendran, Roderick H. Dashwood. Immunomodulatory activity of intermittent low-dose erlotinib plus sulindac: Implications for hereditary and sporadic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5276.