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KCA-ASCO Young Investigator Award

03/04/2007

KCA and the and the ASCO Grants Selection Committee announce the selection of the 2007 Young Investigator Award:

Patricia Tang, MD, Princess Margaret Hospital

Abstract

With the advent of anti-angiogenic therapies (AAT) for cancer treatment, a number of adverse effects have been identified in patients; importantly these include proteinuria (due to disruption of the glomerular filtration barrier) and hypertension.    Hypertension appears to be a class effect of AAT, whereas proteinuria has been reported with bevacizumab, VEGF Trap, and AZD2171.  The physiological mechanisms underlying the hypertension and proteinuria caused by anti-angiogenic therapies are not well understood.

Vascular endothelial growth factor (VEGF)-A expression is maintained in a few specialized microvascular beds in the adult including the kidney glomerulus.  When the VEGF-A gene is deleted from podocytes of adult mice, mice develop proteinuria, hypertension, and glomerular disease.  Strikingly, biopsies taken from 3 patients who developed nephrotic range proteinuria after starting AAT, demonstrate the identical renal lesion.  The similarity between genetic and pharmacologic knockdown of VEGF-A in mice and patients, respectively, suggest that the side effects are due to "on target effects" from anti-VEGF treatment.

This clinical study will characterize the renal and blood pressure changes in patients treated with AZD2171 or VEGF Trap on phase II trials conducted through the Princess Margaret Phase II Consortium.  Correlative studies will investigate three postulated mechanisms: (1) endothelial drop out with reduced medullary flow; (2) reduced prostacyclin, eNOS, prostaglandin E2 with increased thromboxane; and (3) renovascular hypertension.  sFlt1 and steady state drug concentrations will also be explored as possible predictors of development of proteinuria/hypertension.  This research will help determine the most appropriate anti-hypertensive agents to use in this situation, and may lead to a better understanding of hypertension in general as well as other renal disorders such as preeclampsia.

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