Angiogenesis and Tumor Growth

Division Of Clinical Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

We have been interested in developing more effective ways to target the tumor vasculature as a form of cancer treatment. Although the importance of tumor angiogenesis in sustaining tumor growth is clear, the only treatment consists of targeting VEGF/VEGFR. Although the treatment is effective at reducing tumor angiogenesis, a survival benefit is not clear for a variety of reasons, including toxicity and resistance to treatment. However, we believe based on our extensive preclinical studies that the main reason for the limited effectiveness of VEGF/VEGFR targeting is that tumor angiogenesis is sustained by many other factors, besides VEGF. Recently, we identified a panel of factors that appear to play distinct and overlapping roles in inducing and sustaining tumor angiogenesis. It thus became imperative to analyze combinations of drugs that target the tumor endothelium. In one ongoing study, we have found that combining inhibitors of the SHP2 phosphatase, MEK/ERK inhibitors, Ang1/Ang2 inhibitors in combination with VEGF/VEGFR inhibition. Preclinical studies using various combinations of these inhibitors have shown a superior inhibition of tumor angiogenesis and tumor growth. Nonetheless, we have been unable to completely destroy the tumor vasculature and induce complete tumor regression. Therefore, ongoing studies are examining the transcriptome or tumor endothelial cells and tumor cells to identify novel targets for treatment. To do so, we have conducted a spatial transcriptomic analysis of the tumor vasculature and the tumor cells in selected tumor micro-environments to capture endothelial/tumor cell biochemical interactions sustaining cell survival. In a related study, we have analyzed the contribution of bone-marrow derived hematopoietic cells that migrate to tumors and have pro-inflammatory effects results in tumor and endothelial cell growth. In so doing, we have identifies a small population of bone marrow endothelial cells that retain hemogenic potential after birth and can produce myeloid cell populations that are functional as pro-inflammatory cells. This study is currently submitted for publication.