**10. Therapeutic implications of HIF pathway activation in ccRCC**

In the absence of a surgical cure, the outlook for patients with clear cell renal cancer is poor, with a median survival of just 2 years. However, over recent years a number of systemic anti-cancer therapeutic strategies have emerged, which are beginning to alter the outcome for some of these patients.

#### **10.1 Anti-angiogenic therapies**

One strategy has focused on angiogenesis inhibitors to treat metastatic ccRCC. Whilst all tumors require a blood supply to obtain sufficient oxygen and nutrients to grow, ccRCC (and other VHL-dependent cancers such as hemangioblastoma) are particularly rich in blood vessels. Indeed, VEGFA, a master regulator of angiogenesis, [98, 99] is a direct transcriptional target of HIF and is highly expressed in ccRCC cells [41, 140]. Early anti-angiogenic strategies targeted VEGFA using the monoclonal antibody bevacizumab, with limited efficacy [141]. However, several other HIF target genes also encode pro-angiogenic factors, such as PGF, adrenomedullin (ADM) and plasminogen activator 1 (PAI-1), as well as the VEGF receptor, FLT1. These likely act in concert with VEGFA to orchestrate a robust angiogenic phenotype in the context of HIF activation. Therefore, rather than targeting individual factors, more recent strategies have used small-molecule receptor tyrosine kinase inhibitors (TKIs) to block the overarching angiogenic pathways [142]. However, while effective in some individuals, other tumors may fail to respond, likely reflecting heterogeneity in gene expression between tumors. Furthermore, the duration of response may be limited, possibly reflecting intra-tumor heterogeneity and the growth of resistant subclones.

#### **10.2 Immunotherapy**

In recent years, immune checkpoint inhibition via targeting PD-L1 and CTLA-4 has emerged as an effective treatment for advanced ccRCC. This is despite the relatively low mutational burden seen in this type of cancer, which often correlates with sensitivity to immunomodulatory therapy in other cancer types. Whilst HIF has multiple effects on the immune response [143], it is of particular interest that PD-L1 has been found to be transcriptionally regulated by HIF in ccRCC cells [107, 144, 145]. Therefore, it is possible that HIF-mediated activation of PD-L1 may underlie the sensitivity of ccRCC to inhibition of this pathway.
