Monitoring tumour response to extracellular matrix modulation with multiparametric MRI

Abstract

Primary breast tumours are characterised by a dense extracellular matrix (ECM), with accumulation of collagen and hyaluronan (HA). This stromal dense phenotype is associated with tumour progression, metastasis and poor drug delivery. PEGPH20 degrades HA and has been shown to improve tumour response to therapy. Imaging biomarkers which inform on therapeutic efficacy may accelerate development of ECM targeted therapies. This PhD used a pre-clinical multiparametric MRI approach to identify imaging biomarkers that can inform on breast tumour response to PEGPH20. Multiparametric MRI was performed before and after PEGPH20 treatment in three in vivo breast tumour models with different baseline HA accumulation and included MRI relaxometry (T1 and T2), magnetisation transfer (MT) imaging, diffusion weighted imaging (DWI), intrinsic susceptibility MRI (R2*), and MR elastography (MRE). 4T1/HAS3 tumours had the highest baseline HA accumulation. In this model, T1, T2, and the apparent diffusion coefficient (ADC) decreased and MT ratio (MTR) and R2* increased following PEGPH20 treatment. However, T1, T2, MTR and R2* were not significantly different following PEGPH20 in MDA-MB-231 LM2-4 and 4T1 tumours which had lower baseline HA accumulation. There was a decrease in ADC in MDA-MB-231 LM2-4 tumours following PEGPH20, suggesting that this biomarker is the most sensitive to HA degradation. Despite no significant difference in ADC in 4T1 tumours, spatial correspondence between ADC and HA was apparent. The reduction in ADC is likely due to a PEGPH20-induced reduction of the extracellular space. In addition, of all the MRI biomarkers evaluated, ADC had the strongest correlation with percent HA. Tumour viscoelastic properties, measured by MRE, increased following PEGPH20 in MDA-MB-231 LM2-4 breast tumours. Elevated stiffness is associated with tumour progression and so these data suggest a potentially negative effect of PEGPH20. No change in viscoelastic properties was apparent following PEGPH20 in 4T1 and 4T1/HAS3 tumours. In conclusion, this project revealed that ADC is the most sensitive biomarker of HA accumulation and its therapeutic degradation by PEGPH20. In addition, the increase in MDA-MB-231 LM2-4 tumour viscoelastic properties following PEGPH20 may be an early sign of tumour progression and indicate a negative effect of targeting the tumour associated ECM, but further investigation is needed.