Abstract 1229: The advantages of patient-derived orthotopic xenograft (PDOX) of metastatic cervical cancer for individualized therapy compared to the PDX model
Authors: Hiroshima Yukihiko , Zhang Yong , Maawy Ali , Sato Sho , Murakami Takashi , Yamamoto Mako , Uehara Fuminari , Miwa Shinji , Yano Shuya , Momiyama Masashi , Chishima Takashi , Tanaka Kuniya , Bouvet Michael , Endo Itaru , Hoffman Robert M. 
Published: May 2015

Abstract
In this study, we demonstrated the advantage of a patient derived orthotopic xenograft (PDOX) compared to a subcutaneous patient cervical cancer. We originally established the PDX (F1) from the patient with a metastatic HER-2-positive cervical cancer in nude mice. We implanted to the small fragments of F1 PDX to 30 nude mice subcutaneously and 30 nude mice orthotopically to examine the efficacy of various drugs for this tumor. Six weeks after implantation, the mice in each model were randomized to 5 groups and treated in the following groups: (1) Trastuzumab (20 mg/kg, ip, weekly, 5 weeks) + Lapatinib (100 mg/kg, orally, daily, 5 weeks); (2) Entinostat (5 mg/kg, orally, daily, 5 weeks); (3) Trastuzumab (20 mg/kg, ip, weekly, 5 weeks) + Lapatinib (100 mg/kg, orally, daily, 5 weeks) + Entinostat (5 mg/kg, orally, daily, 5 weeks); (4) Carboplatin (30 mg/kg, ip, weekly, 5 weeks); and (5) saline (vehicle/control, ip, weekly, 5 weeks). The relative tumor volume, compared to time zero, of each group in the PDX model was as follows: (1) 1.23 ± 0.50; (2) 3.07 ± 1.79; (3) 0.38 ± 0.18; (4) 0.39 ± 0.23; (5) 10.23 ± 2.91. All regimens had significant efficacy compared to the untreated control group. The Trastuzumab/Lapatinib/Entinostat combination and Carboplatin were the most effective regimens in the subcutaneous model. The relative primary tumor volume of each group in the PDOX model was as follows: (1) 1.00 ± 0.23; (2) 3.25 ± 1.16; (3) 0.54 ± 0.34; (4) 0.48 ± 0.39; (5) 4.45 ± 1.09. The metastatic tumor weight of each group in PDOX model was as follows: (1) 5.7 ± 9.8 mg; (2) 20.1 ± 25.1 mg; (3) 4.7 ± 8.1 mg; (4) 0 ± 0 mg; (5) 112.0 ± 32.5 mg. All regimens had significant efficacy on the primary tumors compared to the control group except for the Entinostat alone group. However, Entinostat alone significantly reduced the metastatic tumor weight compared to the control. The Trastuzumab/Lapatinib/Entinostat combination and Carboplatin were the most effective regimens on both primary and metastatic tumors in the PDOX model. However, only the PDOX model metastasized and could be used to discover the anti-metastatic activity of the Entinostat alone. These results suggest that PDOX is the suitable model for individualized therapy as well as drug discovery for metastatic cervical cancer.
Citation Format: Yukihiko Hiroshima, Yong Zhang, Ali Maawy, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. The advantages of patient-derived orthotopic xenograft (PDOX) of metastatic cervical cancer for individualized therapy compared to the PDX model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1229. doi:10.1158/1538-7445.AM2014-1229