Abstract 89: Development and characterization of a panel of orthotopic glioblastoma multiforme (GBM) patient-derived xenograft (PDX) mouse models for drug efficacy evaluation
Authors: Nielsen Carsten H. , Alfsen Maria Z. , Wick Michael J. , Rundle Melissa , Gudbergsson Johann M. , Jensen Mette M. , Kristensen Lotte K. , Juul Mark U. , Papadopoulos Kyriakos P. , Kjaer Andreas 
Published: August 2019

Background

Glioblastoma multiforme (GBM) is an aggressive cancer type with poor prognosis and survival. The lack of effective treatment may be due to the complex molecular composition and the heterogeneity of the tumors. Subcutaneous patient derived xenograft (PDX) mouse models are widely used in drug development. However, the models fail at modeling the complex microenvironment in the brain and the impact of the blood brain barrier on drug bioavailability. Here we report the development and characterization a panel of orthotopic PDX mouse models.

Methods

Low passage subcutaneous tumors from ten different PDX GBM models (ST108, ST112, ST146, ST545, ST610, ST1388, ST2473, ST3537, ST3713, and ST3720) were implanted orthotopically. Tumor development and growth was monitored by T2-weighted magnetic resonance imaging (MRI). Mice were treated with either temozolomide or vehicle when tumor take was confirmed on an individual basis by MRI. Tumor treatment response was evaluated by MRI, and the final end-point was survival by humane endpoints. Whole brains and tumors were formalin fixed or snap frozen for histological evaluation of markers of invasiveness and cancer stem cells (Nestin, CD44, SOX2, and CXCR4).

In addition, the radiosensitivity of the models was characterized by fractionated external radiation therapy (XRT) delivered as 2 Gy QD x5 or sham in the subcutaneous setting. Expression of EGFR, EGFRvIII, MGMT and mGluR3 were evaluated by qPCR.

Results

The models displayed a wide range in expression levels of EGFR, EGFRvIII, MGMT and mGluR3. Mice treated with XRT showed a variable treatment outcome on both tumor volume and survival. The impact of XRT on prolongation of median survival ranged from 45% to 141%. In the orthotopic setting a variable range of sensitivities was observed in the models ranging from sensitive (ST610 and ST2473) to highly resistant (ST112).

Histologic evaluation showed typical characteristics of GBM tumors such as pseudopalisading cells. Furthermore, cell populations positive for cancer stem cell and invasiveness markers were detected by immunofluorescence imaging.

Conclusion

A panel of GBM PDX models was characterized for several molecular markers and the panel reflected the heterogeneity of human GBM tumors. The models displayed varying sensitivity towards XRT and TMZ.

The established panel of orthotopic GBM PDX models can be used as a platform for testing of new drugs in a setting that more closely mimics the GBM tumor microenvironment and impact of the blood brain barrier.

Citation Format: Carsten H. Nielsen, Maria Z. Alfsen, Michael J. Wick, Melissa Rundle, Johann M. Gudbergsson, Mette M. Jensen, Lotte K. Kristensen, Mark U. Juul, Kyriakos P. Papadopoulos, Andreas Kjaer. Development and characterization of a panel of orthotopic glioblastoma multiforme (GBM) patient-derived xenograft (PDX) mouse models for drug efficacy evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 89.