Abstract 4144: Role of CTGF in hyperthermia resistance in ovarian and uterine cancers

Abstract

Abstract Objective. Even though hyperthermia is a promising treatment for cancer, multiple obstacles remain to be cleared. Among these, the tumor temperatures that must be reached for obtaining clinical efficacy are undefined. The purpose of our study was to identify the molecular predictors of response to hyperthermia in ovarian and uterine cancers. Methods. The temperature transition in tumors during hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer patients was examined. To evaluate sensitivity to hyperthermia, 10 ovarian and uterine cancer cells were treated with hyperthermia and determined median lethal temperature 50 (LT50). An integrative analysis was performed to identify molecules associated with hyperthermia resistance by comparison with gene and protein expression between hyperthermia-resistant (HTR) and -sensitive (HTS) cells. The effect of identified gene silencing on sensitization to hyperthermia and tumor growth in orthotopic models of ovarian cancers by using liposomal siRNA and local hyperthermia by NIR and CuS nanoparticles. Results. The temperature during HIPEC in human tumors was < 40°C even though the perfusion temperature at the entrance was maintained at 42.5°C. Based on LT50, we identified 5 cell lines as HTR (SKOV3, HeyA8, KLE, PEO4, and ES2; LT50 47.5 ± 0.3°C) and 5 as HTS (A2780, A2780CP20, Hec-1A, SKKUT-2, and ISHIKAWA; LT50 45.5 ± 0.2°C). Gene expression studies identified 15 genes that were highly upregulated in HTR compared with HTS cells. Proteomic analyses showed that glucose metabolism-related proteins were down-regulated in SKOV3 cells after hyperthermia. Pathway analysis indicated that FN1, SGK1, and CTGF among the 15 genes were potentially connected with glucose metabolism-related proteins. CTGF siRNA sensitized HTR cells to hyperthermia. The combination of CTGF silencing and local hyperthermia significantly inhibited tumor growth and metastasis in HeyA8 and SKOV3 orthotopic models. Conclusion. Collectively, we identified CTGF as a key target for enhancing response to hyperthermia in ovarian and uterine cancers. Citation Format: Hiroto Hatakeyama, Sherry Y. Wu, Yasmin A. Lyons, Sunila Pradeep, Wanqin Wang, Qian Huang, Karem A. Court, Tao Liu, Song Nie, Cristian Rodriguez-Aguayo, Fangrong Shen, Yan Huang, Takeshi Hisamatsu, Takashi Mitamura, Piotr L. Dorniak, Lingegowda S. Mangala, Marco Petrillo, Madeline Torres-Lugo, Karin D. Rodland, Anna Fagotti, Gabriel Lopez-Berestein, Chun Li, Anil K. Sood. Role of CTGF in hyperthermia resistance in ovarian and uterine cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4144. doi:10.1158/1538-7445.AM2017-4144