journal contribution posted on 2023-04-03, 17:11 authored by Tyler M Foley, Susan N. Payne, Cheri A. Pasch, Alex E. Yueh, Dana R Van De Hey, Demetra P Korkos, Linda Clipson, Molly E Maher, Kristina A. Matkowskyj, Michael A. Newton, Dustin A. Deming
S1. AP spheroids were plated and allowed to mature for 48 hours. S2. To address the issue of potentially slower growth of the spheres with the largest initial sizes, a change-point analysis was performed. S3. AP mice were treated with control (A) or BEZ235 (B) for 14 days. S4. AP mice were treated with BEZ235 or control for 14 days. S5. AP spheroids were treated with NVP-BYL719, BEZ235, LY3023414, or control for 24 hours. S5. AP spheroids were treated with NVP-BYL719, BEZ235, LY3023414, or control for 24 hours. Supplementary Table S1. AP spheroids were treated with NVP-BYL719, GDC0941, BEZ235, LY3023414, or control for 48 hours. Supplemental Table S2. AP mice were treated with BEZ235, LY3023414 or control for 14 days.
University of Wisconsin Carbone Cancer Center (UWCCC)
School of Medicine and Public Health, University of Wisconsin-Madison (UWSMPH)
University of Wisconsin-Madison Graduate School through the Wisconsin Alumni Research Foundation
Funk Out Cancer
HHS | NIH | National Cancer Institute (NCI)
ARTICLE ABSTRACTTherapeutic targeting of the phosphoinositide 3-kinase (PI3K) pathway is an active area of research in multiple cancer types, including breast and endometrial cancers. This pathway is commonly altered in cancer and plays an integral role in numerous vital cellular functions. Mutations in the PIK3CA gene, resulting in a constitutively active form of PI3K, often occur in colorectal cancer (CRC), though the population of patients who would benefit from targeting this pathway has yet to be identified. In human CRCs, PIK3CA mutations most commonly occur concomitantly with loss of Adenomatous Polyposis Coli (APC). Here treatment strategies are investigated that target the PI3K pathway in colon cancers with mutations in APC and PIK3CA. CRC spheroids with Apc and Pik3ca mutations were generated and characterized confirming that these cultures represent the tumors from which they were derived. Pan and alpha isomer-specific PI3K inhibitors did not induce a significant treatment response, whereas the dual PI3K/mTOR inhibitors BEZ235 and LY3023414 induced a dramatic treatment response through decreased cellular proliferation and increased differentiation. The significant treatment responses were confirmed in mice with Apc and Pik3ca mutant colon cancers as measured using endoscopy with a reduction in median lumen occlusion of 53% with BEZ235 and a 24% reduction with reduction with LY3023414 compared to an increase of 53% in controls (p<0.001 and p=0.03, respectively). This response was also confirmed with 18F-FDG microPET/CT imaging. Implications: Spheroid models and transgenic mice suggest that dual PI3K/mTOR inhibition is a potential treatment strategy for APC and PIK3CA mutant colorectal cancers. Thus, further clinical studies of dual PI3K/mTOR inhibitors are warranted in colorectal cancers with these mutations.