A patient RCC-derived murine xenograft model allows better prediction of treatment responses to molecular targeted therapy in patients with advanced renal cancer


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Mei Yi Sim1, Hong Gee Sim1, Tsung Wen Chong1, Weber Lau1, Christopher Cheng1, Hung Huynh2, John SP Yuen1

1Singapore General Hospital, Singapore, 2National Cancer Centre, Singapore, Singapore

Abstract

Background

The choice of molecular targeted therapy for patients with advanced renal cell carcinoma (aRCC) is currently guided by empirical factors such as clinical and histological factors. In addition, biomarkers predictive of treatment responses to targeted therapy are currently lacking. We aim to use a patient RCC-derived xenograft model to develop molecular biomarkers as predictors of tumour responses to molecular targeted therapy in patients with advanced renal cancer.

Method

Patient RCC-derived xenografts were established in SCID mice. The antitumour activity of a range of molecular targeted agents including sunitinib, sorafenib, rapamycin and type-1 insulin-like growth factor receptor (IGF1R) inhibitor, against individual patient-derived RCC xenografts was investigated. Western immunoblotting and immunohistochemical staining were used to detect molecular changes in xenografts in response to therapy.

Results

The uptake rate of RCC xenograft in SCID mice was ~50%. Of the seven xenograft lines (6 clear cell and 1 papillary RCCs), three (2 clear cell and one papillary RCCs) were treated with molecular targeted drugs. All xenografts retain histological characteristics of the tumours they derived from. The clinically used small molecule inhibitors sunitinib and sorafenib exhibited greater anti-tumour activity compared to mTOR and IGF1R inhibitors. In addition, there were variations in treatment responses in individual xenograft treated with different molecular targeted agents currently in clinical use, raising the prospect of individualised treatment for these patients. Besides apoptotic and cell-cycle changes, we found two molecular biomarkers, IGF1R and survivin, the expression of which correlates well with anti-tumour activity of the molecular agents.

Conclusion

This study has shown that a patient RCC-derived murine xenograft model has the potential to help guide molecular targeted therapy in patients with aRCC, which may give rise to individualised and more effective treatment strategy for these patients.