Abstract 3076: Low PTIP expression is linked to HIPEC resistance in appendiceal cancer
Authors: Forsythe Steven D. , Erali Richard A. , Laney Preston , Johansen Allan M. , Sasikumar Shyama , Shen Perry , Levine Edward A. , Soker Shay , Votanopoulos Konstantinos I. 
Published: June 2022

Introduction: Peritoneal carcinomatosis is a late-stage complication of appendiceal cancer, leading to decreased life expectancy and poor quality of life. Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has improved overall survival. Despite this advancement, there remain challenges in determining which patients may benefit from the procedure. Hyperthermia has been shown to potentiate chemotherapy toxicity through interfering with DNA repair, suggesting DNA repair proteins could serve as a predictive marker of clinical outcomes. Herein we applied patient derived tumor organoids (PTOs) to examine the personalized impact of DNA repair mechanisms in efficacy of HIPEC.

Methods: Tumor specimens were obtained from patients undergoing CRS under IRB protocols. Specimens were dissociated and incorporated into a collagen-hyaluronic acid organoid model and treated with clinical HIPEC regimens using mitomycin C (MMC) and oxaliplatin under normothermic (37°C) and heated conditions (42°C) for two hours. The post-treatment viability average responses were aggregated and used for statistical analysis. Treated organoids and tissues were processed histologically and qPCR was performed on patient tumor cells to determine expression of DNA damage markers and DNA damage response.

Results: From June 2019-October 2021, 59 appendiceal tumor tissues from 35 patients with peritoneal carcinomatosis were acquired. 53 PTO groups, from 17 high grade and 36 low grade tumors, were successfully fabricated and tested for HIPEC sensitivity. Hyperthermia potentiated the cytotoxic effect for both MMC (35% vs 57%, p&lt;0.0001, 3/17 HGA and 6/36 LGA PTO sets) and oxaliplatin (41% vs 66%, p&lt;0.0001, 5/17 HGA and 13/37 LGA PTOs). Within the thermosensitive cohort, MMC and oxaliplatin based HIPEC, resulted in similar post perfusion viabilities (35% vs 41%, p=0.25). Furthermore, low and high grade primaries exhibited similar post perfusion viabilities for both MMC (32% vs 40%, p=0.25) and oxaliplatin (36% vs 49%, p=0.08)To test if resistance to HIPEC was associated with increased expression of DNA damage repair proteins in treated organoids, we examined Pax2-Interacting-Protein (PTIP), an important DNA repair protein for both chromatin remodeling and interactions with other DNA repair proteins. Lower PTIP expression in appendiceal tissue sections is correlated with HIPEC treatment sensitivity for both oxaliplatin when compared to high expression (32% vs 49%, p=0.02) and MMC (29% vs 38%, p=0.05). qPCR results confirmed these observations in PTOs, stratifying them into responding and non-responding groups.

Conclusions: Decreased expression of PTIP offers resistance in appendiceal cancer patients treated with HIPEC. PTOs can serve to determine personalized efficacy of HIPEC regimens both at the level of selection of perfusion chemotherapy agent or application of hyperthermia.

Citation Format: Steven D. Forsythe, Richard A. Erali, Preston Laney, Allan M. Johansen, Shyama Sasikumar, Perry Shen, Edward A. Levine, Shay Soker, Konstantinos I. Votanopoulos. Low PTIP expression is linked to HIPEC resistance in appendiceal cancer [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 3076.