Tumour T1 changes in vivo are highly predictive of response to chemotherapy and reflect the number of viable tumour cells – a preclinical MR study in mice

BMC Cancer

Claudia Weidensteiner¹  Peter R Allegrini³  Melanie Sticker-Jantscheff²  Vincent Romanet²  Stephane Ferretti²  Paul MJ McSheehy² 

[1] Department of Radiology Medical Physics, University Medical Center Freiburg, Magnetic Resonance Development and Application Center, Breisacher Str. 60a, 79106 Freiburg, Germany

[2] Oncology Research, Novartis Institutes for Biomedical Research, Basel, Switzerland

[3] Global Imaging Group, Novartis Institutes for Biomedical Research, Basel, Switzerland

关键词: Tumour;    Everolimus;    Animal models;    T₁;    MRS;    MRI;    Biomarkers;   

Others  :  859069
DOI  :  10.1186/1471-2407-14-88

 received in 2013-08-14, accepted in 2014-02-11,  发布年份 2014

【 摘 要 】

Background

Effective chemotherapy rapidly reduces the spin–lattice relaxation of water protons (T₁) in solid tumours and this change (ΔT₁) often precedes and strongly correlates with the eventual change in tumour volume (TVol). To understand the biological nature of ΔT₁, we have performed studies in vivo and ex vivo with the allosteric mTOR inhibitor, everolimus.

Methods

Mice bearing RIF-1 tumours were studied by magnetic resonance imaging (MRI) to determine TVol and T₁, and MR spectroscopy (MRS) to determine levels of the proliferation marker choline and levels of lipid apoptosis markers, prior to and 5 days (endpoint) after daily treatment with vehicle or everolimus (10 mg/kg). At the endpoint, tumours were ablated and an entire section analysed for cellular and necrotic quantification and staining for the proliferation antigen Ki67 and cleaved-caspase-3 as a measure of apoptosis. The number of blood-vessels (BV) was evaluated by CD31 staining. Mice bearing B16/BL6 melanoma tumours were studied by MRI to determine T₁ under similar everolimus treatment. At the endpoint, cell bioluminescence of the tumours was measured ex vivo.

Results

Everolimus blocked RIF-1 tumour growth and significantly reduced tumour T₁ and total choline (Cho) levels, and increased polyunsaturated fatty-acids which are markers of apoptosis. Immunohistochemistry showed that everolimus reduced the %Ki67⁺ cells but did not affect caspase-3 apoptosis, necrosis, BV-number or cell density. The change in T₁ (ΔT₁) correlated strongly with the changes in TVol and Cho and %Ki67⁺. In B16/BL6 tumours, everolimus also decreased T₁ and this correlated with cell bioluminescence; another marker of cell viability. Receiver-operating-characteristic curves (ROC) for everolimus on RIF-1 tumours showed that ΔT₁ had very high levels of sensitivity and specificity (ROC_AUC = 0.84) and this was confirmed for the cytotoxic patupilone in the same tumour model (ROC_AUC = 0.97).

Conclusion

These studies suggest that ΔT₁ is not a measure of cell density but reflects the decreased number of remaining viable and proliferating tumour cells due to perhaps cell and tissue destruction releasing proteins and/or metals that cause T₁ relaxation. ΔT₁ is a highly sensitive and specific predictor of response. This MRI method provides the opportunity to stratify a patient population during tumour therapy in the clinic.

【 授权许可】

   
2014 Weidensteiner et al.; licensee BioMed Central Ltd.

【 图 表 】

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