Uveal Melanoma Patient-Derived Xenografts

Abstract

The prognosis of uveal melanoma (UM) remains poor due to a high risk of metastatic disease. No effective therapies have been described for metastatic UM, and new therapies are needed to improve the outcome for these patients. To achieve this goal, new preclinical animal models are needed. Existing animal models, including genetically engineered mice and orthotopic xenograft models in immunodeficient animals, are inadequate for modelling human disease. In this review, we present the development and characterization of a large panel of UM patient-derived xenografts (PDXs). Based on molecular features as identified in patient tumors, i.e. histopathological classification, specific gene mutations, as well as genomic and gene expression profiles, we show that PDXs closely resemble many important genetic and histological aspects of human UM with a remarkable stability over the course of their in vivo maintenance. Our techniques for establishing and maintaining primary UMs as xenograft tumors in immunodeficient mice provide a high degree of genetic conservation between the primary tumor and its xenograft over multiple in vivo passages. These models therefore represent a significant advance in the resources available for drug screening and studies of the pathogenesis of UM.

Keywords: Gene mutations; Genomic and gene expression profiles; In vivo experiments; Patient-derived xenograft; Uveal melanoma.

Fig. 1

Histopathologic features of two patient tumors and corresponding xenografts. a MM26: patient (mixed cells). b MM26: xenograft (epithelioid cells). c MM66: patient (epithelioid cells). d MM66: xenograft (epithelioid cells). HE. ×200.

Fig. 2

In vivo response to fotemustine. Mice with PDX MP77 (a), MM26 (b), and MM66 (c) were treated with fotemustine intraperitoneally at a dose of 30 mg/kg on days 1-3, every 3 weeks for 3 cycles (closed circles). Controls (open circles) were treated with 0.9% NaCl. Tumor growth was evaluated by plotting the mean of the relative tumor volume ± SD per group.

Fig. 3

In vivo responses of UM xenografts to bendamustine and other chemotherapeutic agents. Mice with PDX MP41 (a), MP46 (b), MP80 (c), and MM26 (d) were treated with bendamustine (11, 13, or 15 mg/kg per injection; closed circles), dacarbazine (open diamonds), temozolomide (closed diamonds), and fotemustine (open circles). Controls (closed squares) were treated with 0.9% NaCl. Tumor growth was evaluated by plotting the mean of the relative tumor volume ± SD per group.