Modes of resistance to anti-angiogenic therapy

Abstract

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are at best transitory and are followed by a restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results: evasive resistance, an adaptation to circumvent the specific angiogenic blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be invoked in different tumour contexts to manifest both evasive and intrinsic resistance, motivating assessment of their prevalence and importance and in turn the design of pharmacological strategies that confer enduring anti-angiogenic therapies.The long-standing proposition that induction of chronic angiogenesis is a hallmark of cancer is now solidly grounded in a substantial body of research involving genetic and pharmacological perturbation of elements in the vascular regulatory circuitry. The 'angiogenic switch'1 is increasingly recognized as a rate-limiting secondary event in multistage carcinogenesis 2 , as documented in animal models of cancer and correlated in advanced pre malignant stages, as well as their malignant derivatives, in a growing list of human cancer types. That this acquired capability is functionally important for manifestation of the disease has been further validated by the approval of angiogenesis inhibitors as cancer therapeutics, most notably ones targeting the vascular endothelial growth factor (VEGF) pro-angiogenic signalling pathways 3 . The pioneers of the clinical proof-of-concept for angiogenesis inhibitors are bevacizumab (Avastin, Genentech/Roche), a ligand-trapping monoclonal antibody, and two kinase inhibitors (sorafenib (Nexavar, Bayer) and sunitinib (Sutent, Pfizer)) targeting the VEGF receptor (VEGFR) tyrosine kinases, principally VEGFR2 (also known as KDR). Since March 2008, bevacizumab has been approved for treating patients with late-stage colon cancer, non-small-cell lung cancer and breast cancer, all in combination with chemotherapy. Sorafenib and sunitinib have both been approved for treating renal carcinoma, a highly vascularized (and angiogenic) tumour type. In addition, sunitinib has been approved for treating gastrointestinal stromal tumours, and sorafenib for hepatocel-lular carcinomas3 -6. Numerous ongoing clinical trials seek to expand the applications of each of these VEGF pathway inhibitors, and dozens of other angiogenesis inhibitors (many also targeting VEGF signalling) are being clinically evaluated (see Angiogenesis Inhibitors Therapy URL and clinical trials URLs in Further information). Moreover, two VEGF pathway inhibitors (the RNA aptamer pegaptanib and a Fab derivative of bevacizumab) have been approved for treating the angiogenic (wet) form of macular degeneration 7-9.Many of the demonstrable clinical benefits and side ef...

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

“…Resistance to therapy is a major limiting factor in the successful treatment of cancers with anti-angiogenic agents that target the VEGF signalling axis (Bergers and Hanahan, 2008;Ebos et al, 2009). Stimulation of tumour angiogenesis by other pro-angiogenic growth factors in the tumour microenvironment may be one mechanism through which this resistance occurs.…”

“…These include growth factors that signal through tyrosine kinase receptors, such as members of the fibroblast growth factor (FGF), placental growth factor (PLGF) and platelet-derived growth factor (PDGF) families and factors that signal through non-tyrosine kinase receptors, such as interleukin-8 (IL-8) and transforming growth-factor-b (Relf et al, 1997;Ferrara, 2002;Presta et al, 2005). These factors may have an important role in the induction of tumour angiogenesis and may also be involved in altering the responsiveness of tumour blood vessels to inhibitors of the VEGF signalling axis (Bergers and Hanahan, 2008). In support of this latter concept, FGF2 is upregulated in a mouse tumour model of acquired resistance to DC101 (a VEGFR2 inhibitory antibody) and inhibition of FGF2 in combination with DC101 led to improved anti-tumour responses (Casanovas et al, 2005).…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…Studies in GEMMs of cancer have begun elucidating the molecular bases of such variation. It has emerged, for example, that certain tumor types are less dependent on VEGF (and hence resistant to VEGF blockade) than others, as they can use noncanonical (e.g., non‐sprouting) modalities of vascular growth or alterative proangiogenic pathways for sprouting angiogenesis (Abdullah and Perez‐Soler, 2011; Bergers and Hanahan, 2008; Leite de Oliveira et al., 2011). For instance, some tumors can grow along pre‐existing blood vessels without evoking an angiogenic response (and indeed are refractory to VEGF blockade); this process is referred to as vascular co‐option (Carmeliet and Jain, 2011a) and is specially observed in well‐vascularized tissues such as the brain (Holash et al., 1999).…”

“…If such vascular subtleties are not recapitulated in transplant tumor models representing a particular organ‐specific cancer, then targeted antiangiogenic drugs may fail to accurately demonstrate their effects and limitations. Additionally, there is clinical evidence for intrinsic resistance (Bergers and Hanahan, 2008) to pharmacological inhibition of the predominant VEGF signaling pathway, seen for example in the progression‐free and overall survival plots of renal cancer patients receiving the VEGF pathway inhibitors bevacizumab (Yang et al., 2003), sunitinib (Motzer et al., 2007) and sorafenib (Escudier et al., 2007), wherein some ostensibly similar patients do not respond at all to the antiangiogenic therapy, and rather continue progressing, apparently refractory to the anti‐angiogenic therapies (Albiges et al., 2011; Garcia et al., 2010; Rini et al., 2008). …”

“…On the other hand, the relative abundance of immunosuppressive T‐regulatory cells (Tregs) (Bates et al., 2006; Pages et al., 2010) or CD4 + effector T‐cells (Denardo et al., 2011; Kohrt et al., 2005; Zhou et al., 2009) can be prognostic of comparatively poor outcome, as can the abundance of various myeloid cell types, including macrophages, neutrophils and immature myeloid cells (Qian and Pollard, 2010; Steidl et al., 2011; Zhou et al., 2009), a subset of which are referred to as myeloid‐derived suppressor cells on account of their ability to inhibit T‐cell functions (Sica and Bronte, 2007). Furthermore, studies in mouse models of cancer have revealed that profuse myeloid cell infiltration correlates with resistance to antiangiogenic therapies targeting the VEGF‐signaling axis (Bergers and Hanahan, 2008; Ferrara, 2010; Squadrito and De Palma, 2011), or accelerated tumor re‐growth following local tumor irradiation (Ahn and Brown, 2008; Kioi et al., 2010; Kozin et al., 2010). Additionally, there is considerable phenotypic and functional heterogeneity among macrophage and neutrophil subtypes, most simply reflected in the amalgam of conventionally or alternatively activated macrophages found in tumors, as well as in inflamed or healing tissues (Biswas and Mantovani, 2010; Coffelt et al., 2010; Gordon and Martinez, 2010; Nucera et al., 2011; Piccard et al., 2011).…”