Oncolytics Biotech Inc T.ONC

ONCY pelareorep (reovirus) down-regulates HIF-1 signaling

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Hypoxia, a condition of insufficient oxygen availability, frequently occurs in solid tumors because of their high oxygen/nutrient demand and abnormal tumor vasculature resulting in a hypoxic TME and stimulation of hypoxia-inducible factor (HIF-1) signaling-in the metastatic cascade.

The systemic administration of ONCY's pelareorep results in the down-regulation of HIF-1 and the conversion of a hypoxic/hostile tumor microenvironment (TME) into one that is conducive for the addition of immune checkpoint inhibitors, like those being combined with pelareorep in the treatment of various solid metastatic tumors, like metastatic pancreatic and breast cancer - as in ONCY's Goblet and Bracelet-1 Phase 2 clinical trials.

Hotani et al. demonstrated that at 120 h post-systemic administration of reovirus (pelareorep), HIF-1 and its target genes were down-regulated. In addition, they inactivated reovirus by UV and observed that the HIF-1 protein level was not altered, proposing that HIF-1 down-regulation was dependent on reovirus replication. 

Additionally Hotani et al. investigated the replication of RV in the hypoxic region of tumors, and found the reovirus capsid protein in the hypoxic region of tumors 120 h after systemic administration of reovirus indicating pelareorep’s ability to overcome the hostile TME while "priming" the innate and adaptive immune system for the administration of immune checkpoint inhibitors, like those referenced above.

More specifically, HIF-1α is related to other variables with a more consolidated predictive and prognostic value on outcome and all these variables are associated with a more aggressive and hypoxic tumor microenvironment. 

ONCY's oncolytic virus pelareorep (reovirus) is able to down-regulate HIF-1α signalling and by doing so is able to convert an otherwise aggressive and hypoxic tumor microenvironment (TME) into one that can promote T cell function, and is conducive for immune checkpoint inhibition, as the AWARE-1 study demonstrated.

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Correspondingly, HIF-1 is also known to be a critical target of digoxin for cancer therapy. Digoxin was reported to inhibit HIF-1α protein synthesis and expression of HIF-1 target genes in cancer cells, and therefore block primary tumor growth, vascularization, invasion, and metastasis. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059749/