Small Molecule Inhibitors of VE-PTP to Mitigate Damage by Radiation Therapy

DESCRIPTION provided by applicant Radiation therapy RT is a mainstay of tumor treatment Despite technical advances that greatly improve the RT targeting collateral normal tissue damage and limited antitumor efficacy remain problematic This is particularly evident when RT involves lung a very radiosensitive organ Following RT an increase in vascular permeability associated with endothelial cell death vascular leak inflammation and angiogenesis contributes to pneumonitis Death of endothelial cells from latent RT damage contributes to the late stages of lung injury hallmarked by fibrosis and reduced vascular density There is no FDA approved agent for protection of lung injury from RT The focus of this proposal is the development of small molecule inhibitors of vascular endothelial protein tyrosine phosphatase VE PTP a protein known to inhibit Angiopoietin Ang Tie signaling VE PTP is expressed predominantly in endothelial cells VE PTP silencing enhances Tie activation promotes endothelial cell survival and inhibits angiogenesis Aerpio has developed potent and highly selective small molecule inhibitors of VE PTP that activate Tie signaling irrespective of the presence of its ligands Angiopoietin and Angiopoietin One of the Aerpio VE PTP inhibitors AKB was shown to enhance the anti tumor effects of RT in a mouse model of breast cancer the effect was associated with vascular normalization and enhanced tumor perfusion We will test the hypotheses that inhibition of VE PTP will reduce RT lung injury Phase and enhance the anti tumor effects of RT by tumor vascular normalization Phase Aim Compare the effect of structurally distinct small molecule VE PTP inhibitors on radiation induced endothelial cell death in vitro and evaluate the pharmacokinetics of the best performing compounds From compounds with subnanomolar Ki six unique compounds were identified based on structural diversity and relative VE PTP inhibitor potency These compounds will be further evaluated in cultured primary ECs in vitro to compare their effects on RT induced endothelial cell death The compound with greatest efficacy and potency for inhibition of RT induced endothelial cell death will be used in Aim Aim Determine the effect of selected VE PTP inhibitors on radiation induced lung injury in vivo Mice will be treated with selected VE PTP inhibitor or vehicle control and then subjected to a single fraction of Gy to the whole thorax Outcome variables assessed at and weeks include pulmonary function studies in vivo imaging using novel NIR markers of blood volume and inflammation and histologic examination Successful demonstration of RT protection of normal lung will provide strong rationale to move forward to Phase Lung damage is the focus here but the results are broadly applicable to many normal tissues Reduction in damage to normal tissue while increasing anti tumor effects of RT can improve quality of life and prolong survival of hundreds of thousands of patients who are treated with RT PUBLIC HEALTH RELEVANCE This proposal seeks to develop a novel class of drugs that simultaneously protect normal tissue while increasing tumor response to radiotherapy Successful drug development will provide significant improvement in quality of life and overall success of radiotherapy which is administered to hundreds of thousands of cancer patients yearly