ABSTRACT
Tumor cells require a robust vascular system to maintain growth and promote invasion (Kerbel 2008). In fact, without appropriate angiogenesis tumors fail to grow beyond 1-2 mm and may remain dormant (Crawford and Ferrara 2009). As early as the 1970’s, insightful pioneers envisioned that the metastatic spread of solid tumors was angiogenesis-dependent (Folkman 1971) suggesting that targeting this process of altered neovascularization would hold great promise in the treatment of solid tumors. Decades later, large clinical trials testing anti-angiogenic agents in lung, kidney, colon, brain and breast cancers have been conducted with a spectrum of responses and proposed clinical benefits. In colon, brain, kidney and lung cancer, anti-angiogenic therapy has been demonstrated to offer clear benefits as both first line (lung, colon) (Hurwitz et al. 2004; Sandler et al. 2006; Reck et al. 2009) and second line therapies (brain, kidney, colon) (Yang et al. 2003; Motzer et al. 2006; Escudier et al. 2007; Escudier et al. 2007; Giantonio et al. 2007; Motzer et al. 2007; Vredenburgh et al. 2007; Norden et al. 2008; Cortes-Funes 2009). These compounds have been used as single agents, though most are approved to be used in concert with other drugs, including immunotherapies and cytotoxic chemotherapies (Ranieri et al. 2006). Angiogenesis is a key component of all tumor cell biology and has recently become a promising therapeutic target for women undergoing treatment for gynecologic cancers (Rasila et al. 2005; Spannuth et al. 2008). Many anti-angiogenic therapeutics target the vascular endothelial growth factor (VEGF) signaling pathway as their primary mechanism of action. The VEGF family includes six related proteins. The most important member is VEGF-A, which was discovered first and was called simply “VEGF” before other variants (VEGF-B, C and D) with more specialized functions involving embryonic and site specific angiogenesis were described. (Li and Eriksson 2001; Kerbel 2008; Fauconnet et al. 2009) VEGF-A will be referenced as simply “VEGF” in this review. Increased VEGF expression
has been hypothesized to result from numerous mechanisms including paracrine control of stromal secretion of circulating VEGF and secretion of VEGF from tumor cells which stimulates neovascularization in an autocrine feedback loop (Hopfl et al. 2004; Monk et al. 2010). While the exact mechanism of activation remains imperfectly understood, VEGF has been established as a key factor promoting endothelial cell migration, fenestration and continuous remodeling of neovascularization in solid tumors (Rasila et al. 2005). Correlative scientific investigations have demonstrated that proangiogenic signaling cascades are activated in ovarian, endometrial and cervical cancer. Molecular alterations that upregulate angiogenic factors such as VEGF, platelet derived growth factor (PDGF) and lesser known molecules have been linked to progression of pre-malignant lesions, advanced and refractory disease, and poor survival. These studies have demonstrated that gynecologic malignancies manifest potent signatures associated with active angiogenesis. Given these data, clinical trials in ovarian, endometrial and cervical cancer analyzing the efficacy of an array of novel antiangiogenic antibodies and small molecules have demonstrated responses in the upfront, recurrent, and consolidation settings. These investigations provide evidence to indicate that a significant subset of gynecologic cancer patients will benefit from therapeutic strategies targeting new blood vessel formation. This chapter will present the pre-clinical data defining common proangiogenic factors in ovarian, endometrial and cervical cancer with a discussion of their underlying biology. These pre-clinical investigations provide rationale for subsequent clinical trials that have employed antiangiogenic strategies to antagonize cancer cell growth. The agents that will be reviewed by disease site will be bevacizumab, VEGF-Trap, sunitinib, sorafinib and pazopanib (Table 1), although many new agents are in the ever evolving pipeline. This innovative therapeutic approach for ovarian, endometrial and cervical cancer has clear and emerging benefits, as well as significant toxicities and costs that need to be addressed both on a patient, as well as societal level.
