Sunitinib for the Treatment of Central Nervous System Glioma

Sunitinib malate (sunitinib) is an orally absorbed small molecule inhibitor of multiple cellular kinases including the family of “Vascular Endothelial Growth Factor Receptors” (VEGFRs), “Platelet Derived Growth Factor Receptors” (PDGFR-alfa and -beta ), c-Kit, FLT1, FLK1/KDR, the FLT3 and RET kinases. Treatment with sunitinib offers a proven survival benefit and is registered for the treatment of patients with advanced renal cell carcinoma and GIST (two respectively HIF/VEGF and PDGFR or KIT dependent cancers) but sunitinib has also demonstrated meaningful anti-tumor activity against a subset of other common cancers (including breast, colon and non-small cell lung cancer). Increased receptor tyrosine kinase signaling involving the VEGF/VEGFR ligand/receptors but also KIT and PDGFR receptor signaling causes profound neo-angiogenesis and may contribute to cellular proliferation and survival of high-grade gliomas (HGG) of the central nervous system (CNS). Furthermore, the KIT, PDGFRa and VEGFR2 genes are frequently amplified and over-expressed in HGG and therefore represent an attractive molecular target for inhibition by sunitinib. Notwithstanding its attractive drug profile, sunitinib has so far not been widely investigated for the treatment of central nervous system glioma. Only recently, the first results from an exploratory clinical trial of sunitinib for recurrent HGG have become available. These early results (obtained with a continuous 37,5 mg/day regimen) indicate that sunitinib has a measurable but transient inhibitory effect on the pathological increase in cerebral blood volume and -flow within recurrent gliomas but that this effect is transient in time and associated with limited clinical benefit. In addition considerable “off target” toxicity (mainly skin and hematological toxicity) were observed that may interfere with further development of sunitinib in this indication. Ongoing phase II studies on sunitinib should further delineate the potential role of this drug in the treatment of CNS glioma at diagnosis and recurrence. Potentially, individual molecular profiling of gliomas to predict their dependence on specified kinase signaling will aid to determine the utility of sunitinib treatment over alternative more specific VEGF(R) targeted agents.