Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate

Abstract

PURPOSE: Tumor 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 standardof-care treatment. EXPERIMENTAL DESIGN: We 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. RESULTS: ITPP 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. CONCLUSIONS: Our 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. DOI: https://doi.org/10.1158/1078-0432. Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-125980 Accepted Version Originally published at: Limani, P; Linecker, M; Kachaylo, E; Tschuor, C; Kron, P; Schlegel, A; Ungethuem, U; Jang, J H; Georgiopoulou, S; Claude Nicolau, C; Lehn, J-M; Graf, R; Humar, B; Clavien, P-A (2016). Antihypoxic potentiation of standard therapy for experimental colorectal liver metastasis through myo-inositol trispyrophosphate. Clinical Cancer Research, 22 (23) Results. ITPP 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 four weeks after treatment cessation. Compared to 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. Conclusions.Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing antic...

Hypoxia‐driven Hif2a coordinates mouse liver regeneration by coupling parenchymal growth to vascular expansion

“…ITPP acts as an allosteric effector of hemoglobin, increasing dissociation of O 2 from heme under low oxygen tension . ITPP efficiently promotes in vivo oxygenation of hypoxic tissues, an effect that lasts for about 2 days following injection . Furthermore, it suppresses Hifs along with the hypoxic response and displays discernable toxicity in neither animals nor humans (http://droia.be/droiacs.html).…”

“…Consequent to its dependence on hemoglobin, ITPP seems to lack direct effects on cells. Testing ITPP on epithelial cell cultures, we have not observed any effects on proliferation, cell death, mitochondrial/glucose metabolism, and migration . Therefore, ITPP represents a unique tool to study the impact a hypoxic environment has on biological processes in vivo .…”

“…Notably, ITPP is considered for the treatment of malignancy, and we have initiated the first clinical trial of ITPP in cancer patients (NCT02528526). In experimental colorectal liver metastasis, we have observed a marked inhibitory effect of ITPP and demonstrated its ability to potentiate standard chemotherapy . ITPP hence might be used for the downstaging of liver tumors to enable resection.…”

“…Notably, ITPP is considered for the treatment of malignancy, (14)(15)(16)(17) and we have initiated the first clinical trial of ITPP in cancer patients (NCT02528526). In experimental colorectal liver metastasis, we have Relative expression of genes encoding endothelial Angpt2 and Tgfb1 after hepatectomy.…”

Impact of myo‐inositol trispyrophosphate (ITPP) on tumour oxygenation and response to irradiation in rodent tumour models

“…Regarding the mechanism, ITPP is an allosteric effector that reduces the oxygen‐binding affinity of haemoglobin and thus facilitates the oxygen release by red blood cells . In addition, long‐term ITPP administration has been shown to lead to vascular normalization through the down‐regulation of HIFs/VEGF with a consequent increase in the oxygen supply to tumours . To determine possible contributing factors to the increase in oxygenation, we assessed the effect of ITPP on tumour perfusion and on cancer cell OCR.…”