CCR Translations Rapid Development of Hypertension by Sorafenib : Toxicity or Target ? □ □ Commentary on

Inhibition of angiogenesis by targeting the VEGF signaling pathway (VSP) has proven to be a successful anticancer strategy in a growing number of solid tumors. Although VEGF signaling is critical for tumor angiogenesis, VEGF also plays important roles in homeostasis of normal vasculature. Early trials reported the development of hypertension in a significant fraction of patients receiving antiangiogenic therapies, particularly those targeting the VSP, but it is becoming clear that nearly all patients experience a rise in blood pressure during therapy, even if they are not diagnosed with hypertension. Despite a growing appreciation of this cardiovascular toxicity, our knowledge of the risk factors for and the mechanisms underlying the development of hypertension on VSP inhibitors, its optimal management, and its potential role as a cancer biomarker is far from complete. In this issue of Clinical Cancer Research, Maitland and colleagues (1) report significant blood pressure elevation on the first day of sorafenib therapy. They detected a mean increase of 8.2 mmHg systolic and 6.5 mmHg diastolic blood pressure within the first 24 h of therapy. The close temporal relationship of blood pressure elevation with sorafenib administration, coupled with the observation that all other VSP inhibitors are capable of inducing hypertension, suggests that this toxicity is a consequence of the VEGF receptor inhibitory property of sorafenib. There was substantial variation in the blood pressure response to sorafenib-from no increase to more than double the mean increase-and this variation was not explained by baseline blood pressure, other clinical variables, or plasma sorafenib levels. Among other things, this study highlights the use of ambulatory blood pressure monitoring (ABPM) as an investigational tool to more accurately measure blood pressure variation in patients receiving VSP inhibitors than can be accomplished with routine office-based measurements. This ability to accurately measure blood pressure response to VSP inhibitors suggests that incorporation of ABPM should facilitate the interpretation of future clinical studies aiming to correlate blood pressure changes with laboratory results and clinical outcomes. The acute rise in blood pressure measured by Maitland and colleagues on the first day of therapy with sorafenib-even before steady-state drug levels are reached-suggests that a primary mechanism by which VSP inhibitors elevate blood pressure is through acute inhibition of endothelial-derived vasodilatory factors such as nitric oxide (Fig. 1). Indeed, direct VEGF infusion induces rapid hypotension, through upregulation of endothelial nitric oxide synthase by PI3k/Aktand MAPK-dependent pathways, resulting in enhanced nitric oxide production and subsequent vasodilation (2). The observation that the majority of blood pressure rise was noted in the first week of sorafenib therapy and normalizes quickly when treatment is held is consistent with the notion that endothelial-dependent vasoconstriction accounts for most of the observed blood pressure elevation. However, preclinical and human evidence indicates that endothelial cell apoptosis, leading to a reduction in capillary density and increased afterload, could also play an important role. Autocrine VEGF provides a survival signal to endothelial cell (3), and in murine renal cancer xenograft models, endothelial cell loss within tumors can be seen as early as day three of VSP inhibitor therapy (4). Furthermore, VSP inhibitors have been noted to induce endothelial cell apoptosis and capillary rarefaction in humans (5), and skin biopsies in patients receiving sorafenib suggest that necrosis at the basal layer occurs, indicating that endothelial cell apoptosis is not just restricted to tumor vasculature (6). Clearly, additional data addressing the mechanism of hypertension in humans treated with VSP inhibitors are needed. Understanding the biologic mechanism that underlies VSP inhibitor-induced hypertension may enable treatment of this toxicity that minimizes potential detrimental antitumor effects. For example, if nitric oxide inhibition plays a primary role in VSP inhibitor-induced hypertension, then restoration of nitric oxide signaling through nitrates or phosphodiesterase Authors' Affiliations: Renal Division, Brigham and Women's Hospital; Lance Armstrong Foundation Adult Survivorship Program, Dana Farber Cancer Institute; Division of Hematology/Oncology, Beth Israel Deaconess Medical Center; and Kidney Cancer Program, Dana Farber/Harvard Cancer Center, Boston, Massachusetts Received 7/23/09; accepted 7/24/09; published OnlineFirst 9/29/09. Requests for reprints: Michael B. Atkins, Division of Hematology/Oncology, Beth Israel Deaconness Medical Center, MASCO Building, Room 412, 375 Longwood Avenue, Boston, MA 02115. Phone: 617-632-9250; Fax: 617-6329260; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1717