SUTENT (SUNITINIB, SU11248)in Patients With Recurrent or Progressive Glioblastoma Multiforme

Background Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in adults and shows an incidence of 5/100.000 inhabitants per year1. In Austria, approximately 350 patients are diagnosed with malignant glioma annually. Advances in surgery, radiotherapy and chemotherapy do only have a minor impact on the natural course of these hardly treatable tumors. The mean survival time of adult patients with GBM is only 9-15 months from the time of diagnosis1,2. Thus, there is an urgent need for more effective therapeutic approaches based on a better molecular understanding of tumor progression and tumor neovascularization.

Molecular Neurooncology has begun to elucidate the complexity of the transformed phenotype of GBM with the goal to identify important molecular changes in the tumor cell that may be amenable for targeted therapies3.

The elucidation of growth factor receptor signaling pathways responsible for the malignant phenotype is now being translated into molecular therapies. At present, targeted therapies with small molecule inhibitors directed against receptor tyrosine kinases (RTKs) or downstream signaling pathways seem to be the most promising therapeutic approaches by directly influencing oncogenetically altered signaling pathways4. Imatinib Mesylate (STI571, Gleevec) is a potent inhibitor of the Bcr-Abl, PDGFR-α/ß, c-Fms and c-KIT tyrosine kinases. Its ability to inhibit PDGFR signaling suggested therapeutic potential in malignant gliomas, but single-agent imatinib showed only minimal therapeutic activity5. Erlotinib (OSI-774, Tarceva) and Gefitinib (ZD1839, Iressa) are potent inhibitors of the Epidermal-Growth-Factor-Receptor (EGFR). However, both inhibitors have also demonstrated only limited activity in GBMs with response rates of 10 to 15% and no significant prolongation of survival6. Tipifarnib (R115777, Zarnestra) is a potent and selective inhibitor of the farnesyl-transferase and influences the Ras oncogene pathway. Overexpression of Ras is implicated in the pathogenesis of malignant gliomas, but also amplified receptors as EGFR, PDGFR and VEGFR can lead to its downstream activation. Clinical trials with inhibition of the Ras signaling pathway showed also only limited biologic effects in GBM patients7.

3.2. Rationale for SUTENT treatment of GBM Patients Reason for the limited activity of selective targeting single agents, but also chemotherapeutic treatments, in GBM patients is the heterogeneity and redundancy of the molecular pathways in glioma cells8. Therefore, a multi-targeted therapy approach, inhibiting multiple molecular signaling pathways involved in tumor progression and tumor neovascularization seems to be a more promising treatment strategy.

SUTENT (SUNITINIB, SU11248) is a potent multi-target inhibitor of VEGFR1-3, PDGFR-α/β, FLT3, c-KIT, RET and CSF-1R. This drug has shown good solubility, bioavailability and protein-binding characteristics9 and was highly effective in metastatic clear-cell renal cell carcinoma (MRCC)10-12 and gastrointestinal stromal tumor (GIST)13,14.

The aggressiveness of GBM is reflected by a diffuse local infiltration into the brain parenchyma and a high tumor vascularization15,16. Neuropathological hallmarks of GBMs are pseudopalisades and microvascular hyperplasia. Pseudopalisades are characterized by an accumulation of hypoxic tumor cells around a central necrosis (Fig. 3A), resulting from increased metabolic demands of tumor cells or vascular occlusion. Such tumor cells express high levels of hypoxia-inducible regulators of angiogenesis, including the hypoxia-inducible factor (HIF)-α. HIF-α accumulates in the tumor cell and binds with its constitutively present partner HIF-β. The HIF complex leads to transcription of hypoxia-induced genes, such as VEGF and PDGF17. These growth factors are secreted into the extracellular space by tumor cells and bind to its high-affinity receptors located on

1. tumor cells (autocrine action), leading to tumor cell proliferation and survival, but also stimulation of the HIF-α protein synthesis and
2. endothelial cells, vascular smooth muscle cells and pericytes (paracrine action), leading to tumor-related neoangiogenesis18-21.

Therefore, VEGF may induce microvascular hyperplasia (Fig. 1B), a typical form of neoangiogenesis immediately related to pseudopalisading cells16,22. Since necrosis and hypoxia are located in the GBM's core, the most biologically relevant hypoxia-induced neovascularization occurs further peripherally, favouring diffuse infiltration by individual glioma cells and allows peripheral GBM expansion.

Summary of molecular and clinical rationales for SUTENT treatment of GBM patients

• The target molecules of SUTENT (i.e. VEGFR, PDGFR, FLT-3, c-KIT, RET) are strongly expressed in GBM tissue and have a crucial role in tumor progression and tumor neovascularization
• The vascular density in GBMs is among the highest of all human neoplasm
• Clinical studies with SUTENT demonstrated a radiological response and a significant improvement in progression free survival due to SUTENT treatment in MRCC and Imatinib-resistant GIST
• In clinical trials using SUTENT the incidence and severity of adverse events and laboratory abnormalities was relatively low (MRCC and GIST patients)