Limited therapeutic efficacy, selectivity and resistance represent the major challenges of targeted-therapy. Unlike other solid tumors, clear cell renal cell carcinoma (ccRCC) constitutively expresses high incidence of hypoxia-inducible factors 1α and 2α (HIFs), and vascular endothelial growth factor (VEGF). This unique profile provided the opportunity to test the hypothesis that inhibition of these targets by optimal dose, schedule, and sequence of agents in combination would result in a treatment modality with greater efficacy and selectivity. This concept was evaluated in 786-0 ccRCC xenografts that constitutively express HIF-2α, but not HIF-1α, treated with methylselenocysteine, topotecan and VEGF/VEGFR-inhibitors alone and in combination. Results generated indicate that treatment of ccRCC xenografts with either methylselenocysteine, an inducer of HIF degradation and modulator of tumor vasculature, or with topotecan, a topoisomerase 1 poison and an inhibitor of HIF synthesis, resulted in significant but incomplete inhibition of HIFs and achieved limited therapeutic benefit. Treatment with a combination of MSC and topotecan administered sequentially when optimal inhibition of HIFs by MSC was achieved resulted in complete inhibition of HIFs and significant increase in response rate, but no cures. Although HIF was inhibited to undetectable levels in individual tumors with the sequential combination of the two agents, the level of VEGF was only partially down regulated. Since ccRCC is known to respond to VEGF/VEGFR-targeted agents, the sequential combination of MSC, prior to and concurrent with protracted and low doses of topotecan and VEGF/VEGFR-targeted agents, resulted in a highly selective and synergistic outcome, with 100% response rates, including 45% cures. In conclusion, the dose, sequence and schedule of HIFs and VEGF/VEGFR inhibitors are critical conditions for optimal therapeutic synergy.
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