Abstract 3227: Advanced imaging with PET and MRI in Temozolomide sensitive and resistant subcutaneous and orthotopic patient-derived xenograft (PDX) glioblastoma models
Authors: Nedergaard Mette K. , Nielsen Carsten H. , Papadopoulos Kyriakos P. , Tolcher Anthony W. , Wick Michael J. , Kjaer Andreas 
Published: August 2015

Background: Patients with glioblastoma multiforme (GBM) have a poor prognosis and few treatment options; hence new treatment strategies are needed. Recently, we adopted standard clinical protocols using magnetic resonance imaging (MRI) and positron emission tomography (PET) with the amino acid PET-tracer (18F-FET) for monitoring of tumor development in orthotopic cell-line GBM models. However, patient-derived xenograft (PDX) models are increasingly used, as they are more predictive of the therapeutic response in patients. Orthotopic PDX models confer a translational advantage as the cancer cells develop in a microenvironment that is similar to the original patient tumor.

The aim of this study was to establish Temozolomide sensitive and resistant subcutaneous and orthotopic PDX GBM models for pre-clinical efficacy studies of new drugs. Furthermore, the performance of 18F-FET PET as an imaging biomarker of therapeutic response was evaluated in the orthotopic PDX models.

Methods: Patient biopsy material from a Temozolomide sensitive (ST610) and a Temozolomide resistant (ST146) patient were implanted subcutaneously in nude mice and tumor growth was measured by caliper after Temozolomide (100 mg/kg/day) or control treatment.

Orthotopic PDX GMB models were established from ST610 and ST146 subcutaneous tumors. Tumors were enzymatically digested and used for intracranial stereotactic injection in nude mice (n = 16 / model). MRI and 18F-FET PET imaging were used to determine tumor take (TT), tumor growth, and treatment response. At confirmed TT, mice were treated with Temozolomide (100mg/kg/day) or control. The primary endpoint was survival. Secondary endpoints were treatment response using MRI and 18F-FET PET.

Results: Temozolomide sensitive and a Temozolomide resistant subcutaneous PDX models were established. Temozolomide inhibited tumor growth in the sensitive model whereas no effect was seen in the resistant model. In addition, contrast enhanced MRI confirmed orthotopic tumor development after implantation. PET imaging as early as two weeks after intracranial implantation detected increased 18F-FET uptake in tumor areas. Finally, response to Temozolomide was followed by 18F-FET PET in the orthotopic models.

Conclusion: The current study confirms the predictive value of the GBM PDX models. By using the orthotopic GBM PDX models, translational imaging techniques can be evaluated and the potential of tracers like 18F-FET as imaging biomarkers of therapeutic response can be assessed. Together, the established subcutaneous and orthotopic PDX models can be used as a relevant translational platform for testing of new drugs.

Citation Format: Mette K. Nedergaard, Carsten H. Nielsen, Kyriakos P. Papadopoulos, Anthony W. Tolcher, Michael J. Wick, Andreas Kjaer. Advanced imaging with PET and MRI in Temozolomide sensitive and resistant subcutaneous and orthotopic patient-derived xenograft (PDX) glioblastoma models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3227. doi:10.1158/1538-7445.AM2015-3227