Establishment of patient-derived tumor xenograft models of mucinous ovarian cancer

Abstract

Mucinous ovarian carcinoma (mEOC) represents a rare subtype of epithelial ovarian cancer, accounting for 3-4% of all ovarian carcinomas. The rarity of this tumor type renders both the preclinical and clinical research compelling. Very few preclinical in vitro and in vivo models exist. We here report the molecular, metabolic and pharmacological characterization of two patient derived xenografts (PDXs) from mEOC, recently obtained in our laboratory. These PDXs maintain the histological and molecular characteristics of the patient's tumors they derived from, including a wild type TP53. Gene expression analysis and metabolomics profile suggest that they differ from high grade serous/endometrioid ovarian carcinoma PDXs. The pharmacological characterization was undertaken testing the in vivo antitumor activity of both cytotoxic agents (cisplatin, paclitaxel, yondelis, oxaliplatin and 5-fluorouracile) and targeted agents (bevacizumab and lapatinib). These newly established mucinous PDXs do recapitulate mEOC and will be of value in the preclinical development of possible new therapeutic strategies for this tumor type.

Keywords: Patient-derived xenografts; chemotherapy; mucinous ovarian cancer.

Figure 1

Mucinous ovarian PDX#164 and PDX#182 (C, D) are representative of the primary tumors of origin (A, B). Immunohistochemical analysis of patient’s tumors and the corresponding PDXs.

Figure 2

Metabolic comparison between mucinous and serous PDXs. Heat map and hierarchical clustering of the deregulated metabolites (A) untargeted (peak intensity); (B) targeted (mM) in high grade serous (#124, #239) and mucinous (#164, #182) PDXs. Each row represents a metabolite, each column the average metabolite intensity/concentration (three biological replicates) for each PDXs. Blue colour indicates lower metabolite level, yellow higher ones.

Figure 3

Drugs antitumor activity in mucinous ovarian cancer PDXs. Tumor bearing nude mice #164 (A) and #182 (B) were treated or not (control mice) -●-; with DDP (cisplatin, i.v., 5 mk/Kg, q7dx3) - -○- -; with PTX (paclitaxel, i.v., 20 mg/Kg, q7dx3) -□-; and yondelis (i.v., 0, 15 mg/Kg, q7dx3) - -■- -. Tumor bearing nude mice #164 (C) and #182 (D) were treated or not (control mice) -●-; with oxaliplatin (i.v., 10 mk/Kg, q7dx3) - - □ -, with 5FU (i.v., 75 mg/Kg in #164, 50 mg/Kg in #182, q7dx3) --○--; with bevacizumab (i.p., 5 mg/Kg, q7dx4) …■…, and with lapatinib (p.o., 100 mg/Kg, 5dx4) …○…. The graphs represent the mean ± SE of each group (8 mices per group).