This invention relates to a polyclonal antibody against a novel phosphorylation site that is known to be correlated with increased tumor growth. Specifically, the antibody targets a phosphorylation site on HIF-1α which is controlled by PIM kinases. This invention can be used not only as a therapeutic against cancer but also potentially as a means for predicting responses to PIM kinase inhibitors during drug development as a way to test the sensitivity to other PIM kinase inhibitors and anti-angiogenic drugs.
Anti-angiogenic therapy is a new and promising strategy for combatting solid cancers including myeloma, leukemia, prostate, and breast cancer. Angiogenesis is considered a hallmark indicator of tumorigenesis and is believed to be required for tumor growth and metastasis. HIF-1 is a master regulator gene involved in the cellular response to hypoxia. Activation of HIF-1 is dependent on HIF-1α and HIF-2α protein levels. Under hypoxic conditions, HIF-1α and HIF-2α protein levels rise due to phosphorylation by PIM kinases which become overexpressed under hypoxic conditions. This leads to further activation of HIF-1 and results in transcription of genes involved in tumorigenesis including angiogenesis.
In attempting to develop effective treatments against solid cancers, it has been shown that prolonged activation of HIF-1 is associated with greater resistance to anti-angiogenic agents. Thus, this invention is a promising approach because it is an antibody that targets the phosphorylation site on HIF-1α to prevent phosphorylation by PIM kinase, thus reducing HIF-1 master regulator activation, and ultimately, decreasing resistance to anti-angiogenic drugs.
- Combination therapy
- Drug development/testing
- Reduce resistance to and increase the efficacy of anti-angiogenic drugs
- Can be used to test the efficacy of PIM kinase inhibitors and anti-angiogenic drugs
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