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

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