Pharmacodynamic and Pharmacokinetic Markers For Anti-angiogenic Cancer Therapy: Implications for Dosing and Selection of Patients

Abstract

Angiogenesis is integral to tumour growth and invasion, and is a key target for cancer therapeutics. However, for many of the licensed indications, only a modest clinical benefit has been observed for both monoclonal antibody and small-molecule tyrosine kinase inhibitor anti-angiogenic therapy. Pre-clinical and clinical studies have attempted to evaluate circulating, imaging, genomic, pharmacokinetic, and pharmacodynamic markers that may aid both the selection of patients for treatment and define dosing. Correct dosing is likely to be critical in the context of vascular normalization to allow better delivery of concomitant anti-cancer therapy and novel imaging techniques hold much promise in the early evaluation of pharmacodynamic response to improve efficacy.

Tumor Hypoxia Regulates Immune Escape/Invasion: Influence on Angiogenesis and Potential Impact of Hypoxic Biomarkers on Cancer Therapies

“…Stable vascular normalization strategies can be aided in their transition from the preclinical to the clinical setting through the availability of biomarkers for patient selection and treatment monitoring. A biomarker is defined based on the clinical question it addresses ( 7 , 127 ). For vascular normalization, biomarkers that can delineate appropriate patient cohorts and that allow monitoring of response are essential for minimizing unwarranted side-effects and maximizing therapeutic efficacy.…”

“…For vascular normalization, biomarkers that can delineate appropriate patient cohorts and that allow monitoring of response are essential for minimizing unwarranted side-effects and maximizing therapeutic efficacy. Hallmarks of vascular normalization entail improved vascular integrity through decreased permeability, and enhanced tumor perfusion, which alleviates tissue hypoxia ( 7 , 127 ). Detecting changes in these phenomena has been accomplished through the determination of several imaging parameters and circulating plasma/serum markers and have recently been reviewed in the context of anti-angiogenic therapy ( 7 , 127 , 128 ).…”

“…Hallmarks of vascular normalization entail improved vascular integrity through decreased permeability, and enhanced tumor perfusion, which alleviates tissue hypoxia ( 7 , 127 ). Detecting changes in these phenomena has been accomplished through the determination of several imaging parameters and circulating plasma/serum markers and have recently been reviewed in the context of anti-angiogenic therapy ( 7 , 127 , 128 ). Herein, we discuss how combinational approaches considering the hypoxic state of the tumor as well as immune infiltration could prove impactful as surrogate biomarkers for the success of vascular normalization.…”

“…BOLD-MRI has recently been used in a colon cancer xenograft model treated with antiangiogenic agents; wherein an increase in the measured oxygen parameter, reflecting hypoxia relief, matched the transient vascular normalization, indicated by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) ( 148 ). DCE-MRI is a technique that has been applied in clinical trials for antiangiogenic therapy ( 127 ), as it enables monitoring tumor perfusion and vascular permeability ( 149 ). Vascular perfusion measured by DCE-MRI was verified to occur in an inverse manner to hypoxia in xenografts of pancreatic ductal carcinoma ( 150 ), patient-derived xenograft models of cervical cancer ( 151 ) and primary liver cancer ( 149 ).…”

Therapy for Cancer: Strategy of Combining Anti-Angiogenic and Target Therapies

“…In recent years, dynamic contrast-enhanced (DCE)-MRI, which enable non-invasive quantification of microvascular structure and function in tumors, has been extensively evaluated in clinical trials as a biomarker for predicting tumor vascular response to anti-angiogenic treatments (Morotti et al, 2017 ). VEGF blockade is believed to reduce tumor vascular permeability and perfusion.…”