Because tumors need a vascular supply for their survival and growth angiogenesis is considered an important therapeutic target in most human cancers including cancer of the central nervous system. patients do not respond to therapy and some receive only modest benefit. Underlying this suboptimal response are multiple mechanisms of drug resistance involving changes in both tumor cells and their microenvironment. In this review we discuss the multiple proposed mechanisms by which neurological tumors evolve to become resistant to antiangiogenic therapies. A better understanding of these mechanisms their context and their interplay will likely facilitate improvements in pharmacological strategies for the targeted treatment of neurological tumors. in the glioma tumor microenvironment [14 16 17 These proangiogenic growth factors will be discussed in further detail in subsequent sections. Antiangiogenic therapies in brain tumors Due to its crucial role in tumor homeostasis VEGF and its signaling was proposed as a therapeutic target in cancer over four decades ago [1]. Since then the United States Food and Drug Administration (FDA) has on the basis of phase III clinical trials approved these brokers for treatment of metastatic colorectal cancer some non-small cell lung cancers renal cell cancer hepatocellular carcinoma and neuroendocrine tumors [18]. More recently in 2009 2009 after a series of phase II clinical trials overcame initial worries of hemorrhage that were associated with FGF6 using these brokers to treat tumors of the central nervous system bevacizumab a VEGF neutralizing antibody was granted accelerated FDA approval for the treatment of recurrent glioblastoma. Antiangiogenic therapies like bevacizumab may even play a role in the treatment of low grade gliomas [19] and in the treatment of benign brain tumors like vestibular schwannomas and meningiomas[3]. In terms of angiogenic pathways targeted in brain tumors the majority of these brokers have targeted the VEGF pathway. As mentioned SBI-0206965 glioma cells have been shown to secrete VEGF to support and increase angiogenesis [20] and comparable changes have been identified in benign brain tumors like vestibular schwannomas and meningiomas [21 22 The VEGF pathway has been targeted in brain tumors and other cancers using two types of brokers (Table 1): brokers targeting VEGF directly or receptor tyrosine kinase inhibitors (RTKIs) that typically target multiple receptor tyrosine kinases. Two examples targeting VEGF include VEGF-Trap (Afibercept) a soluble VEGF receptor and bevacizumab a monoclonal antibody against VEGF-A165 [23]. Examples of RTKIs include sunitib and cediranib (AZD2171) [24]. Table 1 Examples of antiangiogenic therapies for neurological tumors. While the vast majority of antiangiogenic therapies target the VEGF pathway a few pharmacologic brokers have been developed with targets outside this pathway. For example AMG 386 (trebananib) is usually thought to inhibit angiogenesis via SBI-0206965 binding to angiopoietins (Ang 1 and Ang 2) mediators of angiogenesis which will be discussed later [25-27]. Additionally cilengitide is usually a cyclized RGD-containing pentapeptide and a potent antagonist of the αvβ3 and αvβ5 integrins which are upregulated in several SBI-0206965 cancers including glioblastoma and whose activation promotes angiogenesis [25 28 Clinical Observations from use of Antiangiogenic Therapy for Brain Cancers The prototypical VEGF binding agent is usually Bevacizumab (Avastin) which is a humanized monoclonal anti-VEGF antibody and was the first anti-VEGF used in patients with glioblastoma [4]. Several mechanisms of action have been proposed to explain the effectiveness of Bevacizumab in some patients with glioblastoma including direct anti-glioblastoma effects on VEGFR-expressing glioblastoma cells direct inhibition of angiogenesis vascular normalization and perturbation of the glioma stem cell microvascular niche [4]. Additionally Bevacizumab is usually thought to have synergistic potential with chemotherapeutic brokers due to its ability to promote vascular normalization. SBI-0206965 In this process leaky dysfunctional tumor vessels are replaced with vessels of normal integrity causing the originally elevated fluid pressure to normalize. This pressure normalization removes the barrier to fluid influx thereby improving delivery of co-administered chemotherapy [24]. A significant tumor response of glioblastoma to Bevacizumab has been observed in multiple studies and the progression-free survival at 6-months in a recently published article was reported at 42.6% for monotherapy [25 29 Bevacizumab offers a modest (if any) overall survival benefit in patients with.