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The clinical validation of several anti-angiogenic agents targeting the VEGF pathway for the treatment of metastatic colorectal cancer (Hurwitz et al., 2004), non-small cell lung cancer (Sandler et al., 2006), hepatocellular carcinoma (Llovet et al., 2008) and metastatic renal cell carcinoma (mRCC) (Motzer et al., 2009) has provided evidence that angiogenesis inhibition can lead to increased overall patient survival. Although these treatments achieve sustained tumor regression in isolated cases, the average clinical gains from individual therapeutics are measured in only weeks to months. In most patients, cancer progression resumes following initial disease stabilization as tumors acquire resistance to anti-angiogenic agents (Ellis and Hicklin, 2008; Rini and Atkins, 2009). In some disease, such as metastatic breast cancer (Miller et al., 2007), the clinical benefits from VEGF-targeted therapies appear marginal from the outset, while still other cancer types, such as melanoma (Hauschild et al., 2009) and pancreatic ductal adenocarcinoma (Kindler et al., 2007), appear to be refractory to anti-angiogenic drugs from the outset and are deemed “intrinsically” resistant (Bergers and Hanahan, 2008). Acquired and intrinsic resistance to VEGF-targeted therapies stem from multiple proangiogenic mechanisms: VEGF signaling upregulation (Rini and Atkins, 2009); secretion of alternative angiogenic factors (Casanovas, 2011; Kopetz et al., 2010; Loges et al., 2010); acquisition of new blood vessels in an angiogenesis-independent manner via vasculogenesis, vessel co-option or vascular mimicry (Kerbel, 2008; Loges et al., 2010); and activation of stromal components such as myeloid cells and cancer associated fibroblasts, which can cooperate to rescue or expand the tumor vasculature (Bergers and Hanahan, 2008; Crawford and Ferrara, 2009). To overcome acquired resistance mechanisms, some clinicians currently shift patients from one VEGF-targeted therapy to another and are able to achieve lasting clinical benefit at least in the case of metastatic renal cell carcinoma (mRCC), suggesting that upregulation of the VEGF signaling pathway itself is one of the major initial routes of resistance in this cancer type (Rini and Atkins, 2009). However, all cancers eventually acquire resistance to even the most potent VEGF receptor inhibitors, underscoring the need for additional anti-angiogenic therapies targeted at alternative signaling pathways to overcome these resistance mechanisms. In this chapter, we will review two signaling pathways that play critical functions at distinct phases of angiogenesis and against which experimental drugs are currently in development: the NOTCH and BMP9-ALK1 signaling axes. In each case, we will present the genetic and experimental evidence demonstrating the function of these signaling axes in angiogenesis,

Beyond VEGF: The NOTCH and ALK1 Signaling Pathways as Tumor Angiogenesis Targets