Anti-VEGF and beyond: Shaping a new generation of anti-angiogenic therapies for cancer
The class of anti-angiogenic drugs has been one of the very few able to gain international approval for clinical use in oncology in the last decade. Most of the biological and clinical activity of the currently available generation of anti-angiogenic drugs targets VEGF and its related pathways. However, the clinical benefit associated with the use of these drugs has been so far limited, and there is an unmet need for biomarkers able to identify patients who are most likely to benefit and to suggest the best schedule and dosage of these drugs. Here we discuss some of the emerging new combination strategies involving the approved anti-angiogenenic drugs, some of the emerging targets associated with neoplastic angiogenesis, and some novel agents used as a paradigm of the next generation of anti-angiogenic drugs. Introduction Anti-angiogenic drugs bevacizumab, sunitinib, sorafenib and pazopanib have been approved in the past 5 years for the therapy of advanced colo-rectal, breast, lung, kidney and central nervous system cancer (Kerbel, 2008). These drugs, alone or in combination with chemotherapy, have shown in randomized clinical trial to be able to improve overall (OS) or progression-free survival (PFS) in cancer patients. However, the clinical benefit associated with these anti-angiogenic drugs has been so far limited to a few months, and the very large majority (if not all) of the treated patients has suffered clinical progression. Two major drawbacks limit the clinical development of this class of drugs. First, it is still unclear whether the limited impact on patients’ OS and/or PFS is due to the presence of a small clinical benefit in every patient or to the presence of a larger benefit in a subpopulation of patients, an effect to be diluted in large clinical trials enrolling unselected patients. The lack of biomarkers able to select the patients who are most likely to benefit from these targeted drugs (as is for instance
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the presence of the BCR-ABL gene rearrangement for leukemia patients to be treated with imatinib, nilotinib or dasatinib), in fact, hampers a rational use of this class of drugs in adequately selected patient populations where a clinical benefit should be relevant. Second, the same lack of validated biomarkers severely limits the ability to determine optimal biologic dose (OBD) and scheduling of these drugs. Most of the biological and clinical activity of the four anti-angiogenic drugs currently approved for cancer therapy is against the vascular endothelial growth factor (VEGF)-related pathways. Here we discuss how to improve the clinical efficacy of the anti-angiogenic therapy of cancer by describing some innovative approaches, some paradigmatic emerging new targets in neoplastic angiogenesis and the related drugs that might be used in the future along, with, or after anti-VEGF drugs. Mechanisms of resistance to anti-VEGF in neoplasia, and the dilemma of anti-VEGF therapy beyond progression Anti- angiogenic drugs are currently thought to act against neoplasia by four major mechanisms: a) pruning of tumor neovessels, b) vascular normalization (which potentially results in improved delivery of chemotherapy drugs to tumor tissue), c) inhibition of the mobilization of pro-angiogenic cells towards the tumor and d) inhibition of autocrine and paracrine growth factor cross talks between tumor, endothelium and stroma cells. The adaptive mechanisms of resistance to the current generation of anti-angiogenic drugs targeting mostly VEGF, as described by Bergers and Hanahan (2008) and summarized in Fig. 1, are likely to be 1) activation and/ or upregulation of alternative pro-angiogenic signalling pathways within the tumor and/or recruitment of proangiogenic cells, both of which can obviate the necessity of VEGF signalling, thereby effecting reinitiation and continuance of tumor angiogenesis; 2) increased
pericyte coverage of the tumor vasculature, in order to support its integrity and attenuate the necessity for VEGF-mediated survival signalling; and 3) activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without the need for neovascularization. Moreover, there is evidence that certain tumors may have a pre-existing tumor microenvironment supporting intrinsic resistance to antiVEGF therapies. In a recent clinical trial where advanced breast cancer patients were treated with metronomic chemotherapy plus the anti-VEGF antibody bevacizumab (Dellapasqua et al, JCO 2008; Calleri et al, Clin Cancer Res 2009), the risk of relapse was markedly increased in patients who – after two months of therapy – did not achieve a reduction of circulating VEGF levels below a given threshold. This finding – to be confirmed in larger trials - suggests that for the population of patients with high VEGF levels in spite of bevacizumab treatment a possible approach might be to increase to dosage of bevacizumab or to switch towards novel strategies of VEGF inhibition. On the other hand, a large clinical trial has shown that in some cancer patients treated with drug combinations including the anti-VEGF monoclonal antibody bevacizumab, the administration of bevacizumab beyond tumor progression was associated with an improved clinical outcome (Grothey et al, 2008). In the BRiTE study enrolling about 2,000 patients with metastatic colorectal cancer whose first-line therapy consisted of bevacizumab plus chemotherapy, postprogression treatment and survival data for 1,445 patients were obtained, and of those, 642 (44%) continued bevacizumab during second-line treatment. When compared with the 531 patients (37%) who did not receive bevacizumab with their second-line therapy, the median overall survival was 31.8 months versus 19.9 months (hazard ratio 0.48; P <0.001). Even though this OS advantage might well be due to the selection of a subgroup of patients who could tolerate more intense therapy in addition to any therapeutic advantages offered by bevacizumab, these data deserves to be further investigated in a randomized confirmatory trial. Furthermore, adequate preclinical models should be generated and investigated to understand whether a benefit of prolonged anti-VEGF therapy in tumors escaping from therapy does exist and is due to vascular normalization (and better delivery of other antineoplastic drugs) or to an inhibition of cellular and/or molecular pathways other than those directly targeted by the anti-VEGF antibody.
Cell-driven escape from anti-VEGF therapy, and related new therapies in sight. A variety of circulating endothelial and hematopoietic cell populations are known to play a possible role in the generation and maintenance of cancer vessels. Recent evidence also suggests that – at least in mice - a population of myeloid cells may play a crucial role in the escape from anti-VEGF therapies. CD11b+Gr1+ cells are frequently increased in the tumors and in the peripheral blood (PB) of tumor-bearing animals, and have been shown to promote tumor angiogenesis (Shojaei et al, 2009). These cells are also known to suppress immune functions, and have been defined as myeloid-derived suppressor cells (MDSC). In murine models of cancer, MDSCs have a role in mediating refractoriness to anti-VEGF treatment. In fact, MDSCs produce several angiogenic factors including Bv8, a secreted protein previously characterized as an EC mitogen, an hematopoietic growth factor, and as a neuromodulator (Shojaei et al, 2007). Bv8 promotes tumor angiogenesis through increased PB mobilization of myeloid cells such as MDSCs and local stimulation of angiogenesis. Granulocyte colony stimulating factor (G-CSF) was found to be as a strong inducer of Bv8 expression, both in vitro and in vivo. In a recent report, G-CSF and Bv8 were found to have the strongest correlation with refractoriness to anti-VEGF in preclinical tumor models. Treatment with anti-G-CSF antibodies had little or no effect on the growth of tumors sensitive to anti-VEGF therapies, but anti-G-CSF (or anti-Bv8) therapy resulted in reduced tumor angiogenesis and growth, and was additive to anti-VEGF mAb in refractory tumors. Moreover, anti-G-CSF treatment reduced circulating and tumor-associated MDSCs to the levels detected in mice bearing sensitive tumors. Conversely, treatment of mice bearing sensitive tumors with recombinant G-CSF or implantation of G-CSF-transfected cells resulted in increased MDSC numbers and reduced responsiveness to anti-VEGF therapy. These data suggest that the mobilization of proangiogenic cells such as MDSCs involved in escape from anti-VEGF therapy might be targeted with appropriate drugs. This approach needs to be tested in clinical trials, and it remains to be elucidated what is the most appropriate timing (before or after the insurgence of antiVEGF refractoriness?) for such a therapeutic strategy.
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Anti-VEGF and more: the emerging role of combinatory therapies Targeting several interconnected signalling pathways might theoretically result in an increased therapeutic benefit, particularly as the tumor might use alternative
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