• Perparim Limani, Michael Linecker, Ekaterina Kachaylo, Christoph Tschuor, Philipp Kron, Andrea Schlegel, Udo Ungethuem, Jae Hwi Jang, Stavroula Georgiopoulou, Claude Nicolau, Jean-Marie Lehn, Rolf Graf, Bostjan Humar, and Pierre-Alain Clavien.
• Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
• Clin Cancer Res. 2016 Dec 1; 22 (23): 5887-5897.

PurposeTumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standard-of-care treatment.Experimental DesignWe tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential.ResultsITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure.ConclusionsOur findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887-97. ©2016 AACR.©2016 American Association for Cancer Research.

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