Abstract
MRI biomarkers of tumor edema, vascular permeability, blood volume, and average vessel caliber are increasingly being employed to assess the efficacy of tumor therapies. However, the dependence of these biomarkers on a number of physiological factors can compromise their sensitivity and complicate the assessment of therapeutic efficacy. Here we examine the response of these MRI tumor biomarkers to cediranib, a potent vascular endothelial growth factor receptor (VEGFR) inhibitor, in an orthotopic mouse glioma model. A significant increase in the tumor volume and relative vessel caliber index (rVCI) and a slight decrease in the water apparent diffusion coefficient (ADC) were observed for both control and cediranib treated animals. This contrasts with a clinical study that observed a significant decrease in tumor rVCI, ADC and volume with cediranib therapy. While the lack of a difference between control and cediranib treated animals in these biomarker responses might suggest that cediranib has no therapeutic benefit, cediranib treated mice had a significantly increased survival. The increased survival benefit of cediranib treated animals is consistent with the significant decrease observed for cediranib treated animals in the relative cerebral blood volume (rCBV), relative microvascular blood volume (rMBV), transverse relaxation time (T2), blood vessel permeability (Ktrans), and extravascular-extracellular space (νe). The differential response of pre-clinical and clinical tumors to cediranib therapy, along with the lack of a positive response for some biomarkers, indicates the importance of evaluating the whole spectrum of different tumor biomarkers to properly assess the therapeutic response and identify and interpret the therapy-induced changes in the tumor physiology.
Highlights
Biomarkers of tumor response to anti-angiogenic therapy are urgently needed to enable the rapid assessment and tailoring of drug therapies
The control group observed an increase in relative cerebral blood volume (rCBV) (+14.162.3%) and a decrease in relative microvascular blood volume (rMBV) (220.662.1%), again resulting an increased relative vessel caliber index (rVCI)
These biomarkers typically each depend on a number of physiological factors that when altered by tumor therapy may lead to opposing effects on the biomarker response, thereby minimizing the biomarker sensitivity to therapy
Summary
Biomarkers of tumor response to anti-angiogenic therapy are urgently needed to enable the rapid assessment and tailoring of drug therapies. As discussed in more detail below, these MRI biomarkers typically each depend on a variety of physiological factors that may all be influenced by tumor therapy, thereby complicating the interpretation of the biomarker changes. The models used to relate the biomarkers to the relevant physiology may be inadequate or poorly characterized further complicating interpretation of biomarker responses. The MRI biomarker responses are compared with both ex vivo histology and in vivo optical microscopy studies performed previously [20] in the same mouse tumor model to more directly link the biomarkers to the relevant tumor physiology and validate their sensitivity to anti-angiogenic therapy. The results reported here provide insight into which of the MRI biomarkers are most sensitive to changes in tumor morphology and predictive of tumor response to anti-angiogenic therapy
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