Abstract 2970: Lower PTIP expression in appendiceal cancer is linked to oxaliplatin based HIPEC therapy resistance in patient derived tumor organoids
Authors: Steven D. Forsythe, Richard A. Erali, Preston Laney, Shyama Sasikumar, Perry Shen, Edward A. Levine, Konstantinos I. Votanopoulos, Shay Soker
Journal: Cancer Research (2021)

Abstract Introduction: Peritoneal carcinomatosis is a late stage complication of many GI cancers, leading to decreased life expectancy and poor quality of life. The most prevalent treatment type for these patients includes utilizing cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy application (CRS/HIPEC), resulting in a significant improvement in five-year survival. Hyperthermia has been shown to potentiate chemotherapy toxicity through impacting DNA repair. Despite these advancements, there remain challenges in determining which patients will benefit from the procedure, as there are significant costs and morbidities involved in this procedure and patient selection is paramount to success. Objective: Our objective is to determine markers of DNA double stranded break (DSB) repair that may assist in the identification of patients most likely to benefit from this procedure. Methods: Tumor specimens were obtained from patients undergoing CRS according to IRB protocols. Specimens were dissociated and incorporated into an ECM-based hydrogel system and biofabricated into 3D tumor organoids. Organoids were treated with HIPEC regimens with variations in treatment, dose, temperature and time to determine optimal conditions. The averages of patient responses were aggregated and used for statistical analysis. Treated organoids were processed histologically to determine expression of DSB repair markers. Results: From June 2019- November 2020, 41 (26 appendiceal and 15 colorectal) patient tumors were acquired, with 32 (21 appendiceal and 10 colorectal) successfully yielding tumor organoids. The application of heat was a significant factor in determining two-hour, lower dose oxaliplatin effectiveness for both tumor types (p=0.01 and p=0.036, respectively). Drug testing reveled no statistical difference between heated mitomycin C (MMC) and oxaliplatin regimens of two-hour duration for appendiceal (26% vs 31%, p=0.35) and colorectal patients (38% vs 29%, p=0.47), Lower dose, longer duration oxaliplatin treatments were more effective than high dose, shorter duration treatments for both appendiceal (31% vs 57%, p&amp;lt;0.001) and colorectal tumors (29% vs 67%, p=0.04). MMC regimens were most effective on a per patient basis for appendiceal tumors (15/21 patients), whereas lower dose, two-hour oxaliplatin regimen treatments were most effective for colorectal tumors (7/11). Lower PTIP expression in appendiceal tissue sections is correlated towards heated treatment resistance for two-hour oxaliplatin treatments (p=0.02) Conclusions: Patient derived organoids can be utilized to determine optimal HIPEC regimens, with responses to temperature, duration and treatment varying between patients. Further analysis of DNA DSB markers is ongoing, with initial results appearing to stratify patients into responding and non-responding categories. Citation Format: Steven D. Forsythe, Richard A. Erali, Preston Laney, Shyama Sasikumar, Perry Shen, Edward A. Levine, Konstantinos I. Votanopoulos, Shay Soker. Lower PTIP expression in appendiceal cancer is linked to oxaliplatin based HIPEC therapy resistance in patient derived tumor organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2970.