Prognosis remains grim for pediatric patients with high-risk, malignant solid tumors. Children with malignant tumors and children undergoing hematopoietic stem cell transplantation (HSCT) have significant morbidity and mortality due to chemotherapy-induced toxicities. Novel biomarkers based on a distinct biologic profile and on response to therapy are needed to develop individualized therapies and response assessments. Angiogenesis markers have emerged as promising candidates in adult trials. However, pediatric studies are scarce. Our long-term objectives are to identify novel angiogenesis biomarkers in children to promote individualized chemotherapy and to facilitate development of novel therapies. Angiogenesis is coordinated via complex genetic and cellular mechanisms. Vascular endothelial growth factor A (VEGFA), a major growth factor regulating angiogenesis, is encoded by a highly polymorphic gene. Multiple studies demonstrate a correlation between VEGFA genotype and diseases with altered angiogenesis. A major cellular component regulating angiogenesis is circulating endothelial progenitor cells (EPCs). EPCs facilitate endothelial repair and vascular remodeling. Reduced EPCs correlate with clinical indices of endothelial dysfunction and increased risk of vascular disease. Though labeled EPCs, these are hematopoietic progenitors that originate from the bone marrow, not endothelium. Thus, myelotoxic therapies will impact EPCs with subsequent implications for normal and pathologic angiogenesis. Recent advances in flow cytometry allow for enumeration of angiogenic (circulating progenitor cells, CPCs) and non-angiogenic (non-CPCs) progenitors, using blood volumes amenable for implementation in pediatric studies. Our overall hypothesis is that interindividual variability in circulating EPC subsets after chemotherapy will serve as a biomarker for efficacy of malignant solid tumor therapy as well as to predict toxicity after HSCT. In this proposal, we will examine inter-individual variability in chemotherapy response and angiogenesis markers in children. We propose to assess novel angiogenesis markers that include EPC subsets, VEGF genetic heterogeneity, and microvessel density.
This research is important for improving the effectiveness of anti-cancer drugs to eradicate childhood malignancies and at the same time reduce toxicities of these drugs. This research proposes to combine genetic factors together with a child's response to drugs to individually tailor future anti-cancer drug treatments.
|Hennessy, S; Flockhart, D A (2012) The need for translational research on drug-drug interactions. Clin Pharmacol Ther 91:771-3|