Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

/pdf/imaging-biomarker-roadmap-for-cancer-studies-4h34ouolr8.pdf

Imaging biomarker roadmap for cancer studies.

Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large- and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1α and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype.

https://www.pnas.org/content/pnas/108/9/3749.full.pdf

Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma

Vascular and angiogenic processes provide an important target for novel cancer therapeutics. Dynamic contrast-enhanced magnetic resonance imaging is being used increasingly to noninvasively monitor the action of these therapeutics in early-stage clinical trials. This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used.

/pdf/the-assessment-of-antiangiogenic-and-antivascular-therapies-4c0jsr6z43.pdf

The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is now frequently used in early clinical trial assessment of antiangiogenic and vascular disrupting compounds. Evidence of drug efficacy and dose-dependent response has been demonstrated with some angiogenesis inhibitors. This review highlights the critical issues that influence T(1)-weighted DCE-MRI data acquisition and analysis, identifies important areas for future development and reviews the clinical trial findings to date.

/pdf/dce-mri-biomarkers-in-the-clinical-evaluation-of-14rlje6b3l.pdf

DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents

The role of neuroimaging in patients with brain tumors is no longer simply to evaluate structural abnormality and identify tumor-related complications. By transitioning from a purely anatomy-based discipline to one that incorporates functional, hemodynamic, metabolic, cellular, and cytoarchitectural

http://www.ajnr.org/content/ajnr/27/3/475.full.pdf

Update on Brain Tumor Imaging: From Anatomy to Physiology

MRI is increasingly being used to evaluate antiangio-genic and antivascular agents in early stage clinical trials.The measurement and analysis methodology required forrobust application of MRI to such trials has beenconsidered by specialist panels in a workshop, resultingin recommendations for the design and analysis of trials,and identiﬁcation of areas requiring further development.The following document is the text of the poster presentedbyCancerResearchUKPharmacodynamic/PharmacokineticTechnologies Advisory Committee (PTAC) on the use ofMRI for the evaluation of antiangiogenic and antivascularcancer drugs presented at the American Association forCancer Research, Washington (2003) and at the Inter-national Society of Magnetic Resonance in Medicine, 11thScientiﬁc meeting, Toronto, 2003 [1, 2].

Assessment of antiangiogenic and antivascular therapeutics using MRI: recommendations for appropriate methodology for clinical trials.

Assessment of anti-angiogenic and anti-vascular therapeutics using Magnetic Resonance Imaging: recommendations for appropriate methodology for clinical trials.

R Rathbone

Papers

The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations

Assessment of antiangiogenic and antivascular therapeutics using MRI: recommendations for appropriate methodology for clinical trials.

Assessment of anti-angiogenic and anti-vascular therapeutics using Magnetic Resonance Imaging: recommendations for appropriate methodology for clinical trials.