br Other Strategies for HIF

Other Strategies for HIF-α Inhibition NSC-644221 is another HIF-α inhibitor acting at the translational level, independently of proteasomal degradation and VHL status, and is devoid of DNA damage-inducing properties [70]. NSC-644221 arrests TMC120 in G2–M through a cell type-specific Topo-2-dependent mechanism [70]. Interestingly, cell type-specificity was lost whenever the drug was combined with a histone deacetylase inhibitor, suggesting that cell-specificity is determined by epigenetic factors [71]. Another approach blocking HIF-α in human cancers is the administration of antisense oligonucleotides. EZN-2968 (also known as RO7070179) is a HIF-1α-specific intravenous targeting agent shown to decrease HIF-1α levels in four out of six patients with refractory advanced solid tumors in a small patient cohort [72]. More recently, Pan et al. devised a paralog-selective strategy by using poly(lactic-co-glycolic) antisense oligonucleotide nanoparticles that impaired HIF-2α expression, hypoxic CC proliferation, tumor growth, and angiogenesis in pancreatic cancer models [73]. Interestingly, HIF-2α is the predominant paralog in RCCs, in which it upregulates VEGF-A, resulting in hypervascular tumors sensitive to VEGF-A or VEGFR blockade [74]. Consistently, clinical trials showed that bevacizumab or RTKI monotherapies significantly improved PFS and sometimes OS in advanced or metastatic RCC [74,75]. PT2399, a novel HIF-2α antagonist impairing HIF-2α:HIF-1β dimerization, displayed promising antitumor properties in PDXs and metastatic RCCs, while outperforming the antitumor and AA efficacy of sunitinib [76,77]. However, the same study provided evidence of PT2399 therapy resistance associated with loss of p53 activity independently of HIF-2α heterodimerization blockade [76,77]. Nevertheless, these results suggest that the usage of paralog-specific HIF-α blockade holds significant potential to manipulate the hypoxic tumor microenvironment to decrease or eliminate resistance and metastases. PT2385 is a PT2399 analog currently undergoing Phase 1 testing in RCC as monotherapy and combined with the PD-1 immune checkpoint inhibitor nivolumab (NCT02293980). Another promising strategy for HIF-α blockade is the repurposing of FDA-approved drugs inhibiting HIF-α activity in vitro and in preclinical models; these compounds include cardiac glycosides, anthracyclines, and acriflavine (Box 4).
Combinatorial AA and HIF-α Inhibition Therapy LDM topotecan enhances antitumor efficacy when administered in combination with pazopanib or sunitinib in several preclinical models [50,78–81], an effect attributed at least in part to prevention of HIF-α induction by AA therapy. Consistently, combination of LDM topotecan with pazopanib or sunitinib decreased HIF-1α levels, tumor growth, and vascularization in triple-negative breast CCs, while significantly increasing survival in mouse models of advanced metastatic breast cancer [50]. In another study, topotecan and bevacizumab decreased tumor growth, IH, HIF-1α, and angiogenesis in glioma xenografts [82]. Pham et al. compared the efficacy of bevacizumab or CRLX101 monotherapy against the combination of both drugs, showing that CRLX101 and bevacizumab monotherapy similarly decreased HIF-1α, hypoxia, and MVD in metastatic triple-negative breast cancer orthografts [61]. An equivalent synergy was observed when CRLX101 was combined with either aflibercept or pazopanib. Importantly, LDM administration of CRLX101 or CRLX101/bevacizumab delayed intraperitoneally implanted ovarian CC growth mimicking advanced ovarian cancer, while blocking HIF-1α and improving survival; by contrast, bevacizumab monotherapy showed minimal efficacy associated with increased HIF-1α expression [62]. In another study, Jeong et al. evaluated the effect of the nanoparticle irinotecan formulation, EZN-2208, when combined with bevacizumab in ten patients bearing refractory solid cancers. Data showed that EZN-2208/bevacizumab decreased HIF-1α protein levels and target gene transactivation in five out of seven patients compared with bevacizumab alone. However, likely due to the small sample size, the authors did not detect a correlation between HIF-1α levels and therapeutic responses [83]. These data warrant further studies focused upon the molecular mechanisms mediating the beneficial effects of added HIF-α blockade upon AA therapies; moreover, larger randomized studies are needed to assess the clinical efficacy of this approach. In addition, these data suggest that LDM chemotherapy, and RTK and topoisomerase inhibitors have additive or synergistic effects on HIF-α signaling, thus negating the effect of IH in tumor progression.