Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)
- Role of HIF in clear cell renal carcinoma
- Cooperating events
- Treatment of renal cell carcinoma: HIF antagonists
- Treatment of renal cell carcinoma: mTOR inhibitors
- Treatment of renal cell carcinoma: angiogenesis inhibitors
- Treatment of renal cell carcinoma: tumor cell receptor tyrosine kinases
- Other targets
- Carbonic anhydrase and lactate dehydrogenase
- Histone methylases and demethylases
Renal cell carcinoma is one of the most angiogenic solid tumors. Indeed, renal angiography was once an important tool to diagnose this neoplasm. Renal cell carcinoma hypervascularity reflects the overproduction of HIF-dependent angiogenic factors such as VEGF. Notably, the remarkable upregulation of VEGF observed upon pVHL loss, and consequent increase in new blood vessel production, probably diminishes the selection pressure to upregulate additional angiogenic factors in this setting. In contrast, a host of angiogenic factors in addition to, or instead of, VEGF likely contributes to neoangiogenesis associated with other solid tumor types.
In keeping with this view, a variety of drugs that inhibit VEGF, such as bevacizumab, or its receptor KDR, such as sorafenib, sunitinib, axitinib, and pazopanib, have now demonstrated significant activity in the treatment of renal cell carcinoma and were approved by the FDA [193–197]. These agents induce significant disease stabilization and, in some cases, frank regressions. Newer VEGF inhibitors that are more potent, more specific, or both are in various stages of development. It is anticipated that greater potency will translate into greater clinical efficacy although there might be limits regarding the degree to which VEGF signaling can be safely interrupted in man. Microangiopathic hemolytic anemia was observed in patients in which two VEGF inhibitors were combined [198, 199], and both preclinical and clinical data suggest that chronic VEGF inhibition could lead to cardiomyopathic changes [200, 201]. Developing VEGF inhibitors that exhibit greater specificity is important because some of the existing agents are difficult to combine with other agents, presumably because of their off-target effects. The history of curative cancer therapy suggests that the eventual cure of renal cell carcinoma will require a combination of agents that have novel mechanisms of action and that are non-cross resistant. A VEGF inhibitor will probably be cornerstone of such a combination.
In the simplest view, pVHL status would serve as a predictive biomarker, with VEGF inhibitors being more active in pVHL-defective renal cell carcinomas than in pVHL-proficient tumors. Although some studies support this contention, others do not [202–205]. This lack of consistency might be due, at least partly, to technical differences related to how pVHL status was determined and how therapeutic response was measured. It appears that the vast majority of clear cell renal carcinomas (especially those that do not exhibit mixed histological patterns with areas of non-clear cell features) have transcriptional signatures indicative of pVHL inactivation and HIF activation, including some without demonstrable VHL mutations or hypermethylation . Studies with newer sequencing platforms suggest that some of these tumors do, indeed, have VHL mutations that would be missed using conventional DNA sequencing approaches [4, 7]. Suffice it to say that VHL status is not currently a sufficient robust predictive biomarker to be used in clinical decision-making.
Platelet-derived growth factor B (hereafter called PDGF) is another well-studied HIF target [206, 207]. PDGF supports the expansion of pericytes that surround new blood vessels and provide survival signals to the associated endothelial cells. In preclinical models, newly sprouting blood vessels that lack pericyte coverage are more sensitive to VEGF blockade than are more mature vessels that are associated with pericytes [208–210]. This might explain why the objective tumor response (regression) rate in renal cell carcinoma is higher with small-molecule KDR inhibitors, many of which inhibit PDGFR, than with bevacizumab, which solely inhibits VEGF. On the other hand, it should be borne in mind that PDGFR inhibitors such as imatinib mesylate have not yet demonstrated utility as single agents in renal cell carcinoma and have not been shown to enhance the activity of bevacizumab [211–213]. Moreover, many of the existing KDR inhibitors might have off-target effects other than PDGFR inhibition that fortuitously contribute to their antitumor activity.
VEGF inhibitors, although highly active in renal cell carcinoma, are not curative as single agents, and renal cell carcinoma patients treated with these agents will eventually experience disease progression. The mechanisms underlying de novo or acquired resistance to VEGF inhibitors are poorly understood at the molecular level. One study suggested that upregulation of the angiogenic cytokine IL-8, which cooperates with VEGF in some settings , contributes to resistance to VEGF inhibitors  and IL-8 polymorphisms and circulating IL-8 levels have been linked to clinical outcomes in patients treated with VEGF inhibitors [216, 217]. Interestingly, IL-8 is regulated by HIF and NFkB, both of which are controlled by pVHL [214, 218–222] (Fig. 3.3). These considerations warrant exploration of inhibitors of IL-8, or its receptors CXCR1 and CXCR2, in renal cell carcinoma.
The receptor tyrosine kinase TIE2 plays an important role in angiogenesis . Activation of TIE2 by ligands such as angiopoietin 1 stabilizes blood vessels, while antagonists such as angiopoietin 2 destabilize blood vessels, rendering them permissive for sprouting and new blood vessel formation but also hyperdependent on VEGF as a survival factor. Although there have been conflicting reports on the regulation of angiopoietins by pVHL [224, 225], knowledge of TIE2 biology suggests that dual inhibition of VEGF and TIE2 might block angiogenesis more effectively than would VEGF blockade alone. Circulating levels of a soluble form of TIE2 have also been touted as a means of monitoring antiangiogenic therapy in this patient population .
Unfortunately, the TIE2 antagonist AMG386 in combination with the VEGFR inhibitor sorafenib was not more active than sorafenib alone .
CXCR4 and SDF
Both CXCR4 and its ligand, CXCL12/SDF, are HIF targets and upregulated in pVHL-defective tumors [228, 229]. In some mouse models, blocking CXCR4 inhibits the recruitment of circulating bone marrow-derived cells that can contribute to new blood vessel formation and can enhance the antiangiogenic activity of VEGF inhibitors . CXCR4 might also play cell autonomous roles in renal cell carcinoma invasion and metastasis. In this regard, neutralizing antibodies to CXCL12 were shown to decrease metastasis, without affecting angiogenesis, in an orthotopic renal tumor model in mice . Conversely, upregulation of CXCR4 on an epigenetic basis was associated with increased renal cell carcinoma metastasis .
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