Abstract 5631: Immunomodulatory activity of sulindac plus erlotinib for colon cancer prevention in familial adenomatous polyposis

Abstract

Abstract Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by germline mutation in Adenomatous Polyposis Coli (APC)1. Patients with FAP have a nearly 100% lifetime risk of colorectal cancer (CRC) due to the formation of hundreds to thousands of adenomatous polyps in the gastrointestinal tract2. A clinical trial in FAP patients demonstrated that Cox-1/2 inhibitor sulindac (SUL) plus EGFR inhibitor erlotinib (ERL) reduced polyp burden significantly in the colon and small intestine (SI), but toxicity issues raised concerns for durable long-term CRC interception3. In the Apc-mutant polyposis in rat colon (Pirc) rat model of FAP, we determined low-dose regimens of ERL+SUL that were both safe and efficacious4. In the current investigation, the lowest tested dose of dietary SUL (125 ppm continuously) plus ERL (5 mg/kg twice weekly), given at one-half the SUL clinical dose and one-fourth of the ERL clinical dose, administered for 46 weeks respectively, demonstrated good inhibition of tumor burden in the colon (>85% efficacy, p<0.05) and SI (>94% efficacy, p<0.05) compared to untreated controls. Moreover, treatment normalized organ weights and hematocrits that were altered in the untreated AIN controls.Recently, ERL5 and SUL6 were individually demonstrated to increase the recruitment of inflammatory immune cells in mouse models of lung and colon cancer, respectively. However, ERL+SUL in combination was not investigated in the context of immune cell infiltration and polarization. Our preliminary IHC data in the Pirc model indicated increased recruitment of CD8+ T cells in colon polyps by SUL 250 ppm + ERL 42 mg/kg once a week. RT-qPCR and immunoblotting analysis of colon polyps obtained from the low-dose combination of SUL 125 ppm + ERL 5 mg/kg twice weekly demonstrated increased CD4 expression and concurrently decreased oncogenic IL-17 expression and tumor associated macrophage markers (CD163 and CD206) (P<0.05 vs control). Additional immune markers will be identified and validated via CyTOF. We hypothesize that low-dose combination of SUL+ERL can enhance the recruitment of immune cells into early adenomatous colon and SI polyps, providing an effective immunointerception strategy, with potential clinical relevance for FAP patients before or after colectomy. Acknowledgements Research supported by NCI Contract Number 75N91019D00021, Task Order 75N91019F00130. 1.Groden J et al., Cell 1991; 66:589-600.2.Jasperson KW et al., Gastroenterology 2010; 138:2044-2058.3.Samadder NJ et. al., JAMA 2016; 315:1266-75.4.Ulusan AM et. al., Cancer Prev Res (Phila). 2021; 14:325-336.5.Ayeni D et al., J Immunother Cancer 2019; 7:172.6.Yi B et al., Mol Cancer Ther 2021; Apr 20. Citation Format: Chakrapani Tripathi, Roderick H. Dashwood. Immunomodulatory activity of sulindac plus erlotinib for colon cancer prevention in familial adenomatous polyposis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5631.