Abstract
The HDAC inhibitor abexinostat was well tolerated in combination with the VEGFR inhibitor pazopanib.
Major finding: The HDAC inhibitor abexinostat was well tolerated in combination with the VEGFR inhibitor pazopanib.
Concept: Abexinostat promotes an epigenetic downregulation of VEGF and HIF1α to sensitize cells to pazopanib.
Impact: Abexinostat in combination with pazopanib may lead to durable responses in advanced solid tumors.
The multikinase inhibitor pazopanib is approved for the treatment of renal cell carcinoma (RCC) and soft-tissue sarcomas. Pazopanib inhibits VEGFR and other growth factor receptors, but the duration of response is limited because hypoxia drives a histone deacetylase (HDAC)–mediated upregulation and stabilization of HIF1α that promotes VEGF expression. Thus, HDAC inhibitors have been shown to downregulate HIF1α and synergize with pazopanib in refractory cancer cell lines. Aggarwal and colleagues performed an open-label, dose-escalation/expansion phase Ib study evaluating abexinostat plus pazopanib to determine if the combination can reverse resistance to pazopanib and other VEGF-targeting therapies in patients with advanced solid tumors. A total of 51 patients were enrolled, including 36 patients with any solid tumor in the dose-escalation phase and 22 with RCC in the dose-expansion phase. The primary objective was to determine the maximum tolerated and recommended phase II dose and schedule of abexinostat in combination with pazopanib. No dose-limiting toxicities were observed at the determined recommended phase II dose and schedule. In total, 9 patients (21%) achieved an objective response (6 with RCC, 2 with thyroid cancer, and 1 with mesothelioma). Of the 10 patients who had progressed on pazopanib monotherapy, 7 (70%) experienced tumor regression, and of the 28 patients who progressed on prior VEGF-targeting therapies, 19 (68%) experienced tumor regression, including 6 objective responses. The median duration of response was 9.1 months, indicating durable responses. HDAC2 expression and histone acetylation in the peripheral blood were associated with durable responses to treatment. Collectively, the results of this phase I trial suggest that HDAC inhibition may promote an epigenetic reversal of resistance to VEGF pathway inhibitors and that the combination of abexinostat and pazopanib warrants further clinical investigation in patients with solid tumors.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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