Unmet NeedThe present invention could be used for treatment of any solid tumor, including ovarian, breast, melanoma, lung, colon, pancreas, liver, esophageal, stomach, epithelial, sarcoma, cervical, and uterine. This encompasses a huge market size and compelling unmet need. The effectiveness of this combination therapy has been demonstrated specifically in models of ovarian cancer. While ovarian cancer has a relatively low incidence rate, it has a five-year survival rate of only 44%, making it the most-deadly gynecologic malignancy. One of the most challenging aspects of ovarian cancer treatment is that it is immunosupressive: the tumor microenvironment is infiltrated with myeloid-derived suppressor cells (MDSCs) and regulatory T-cells. The present invention addresses the need to overcome this immunosupression to activate the immune system at the tumor site. This strategy has been effective against ovarian cancer, but could be applied to solid tumors of many types.
Technology overviewJohns Hopkins researchers found that a mouse model of ovarian cancer treated with a combination of a DNA methyltransferase inhibitor (DNMTi) and an ornithine decarboxylase inhibitor (ODCi) showed reduced tumor burden and prolonged survival. DNMTis, such as 5-azacytidine (AZA), are an established anti-cancer strategy that have been recently shown to upregulate immune signaling in cancer by triggering a type I interferon response. Ornithine decarboxylase catalyzes a rate limiting step in the synthesis of polyamines, which have an important antioxidant role in the cell. The inventors previously showed that AZA treatment can increase recruitment of immune cells to the tumor, and hypothesized that the addition of an ODCi could have a synergistic effect. In the mouse model of ovarian cancer, mice treated with AZA and the ODC-inhibitor DFMO show an increases number of total immune cells, a reduction in cells that suppress the immune response, and an increase in the percentage of activated immune cells compared with mice treated with AZA alone, DFMO alone, or a mock treatment. In other cancers, new DNMTis or ODCis could be substituted for AZA and DFMO, and HDAC inhibitors could be added.
Stage of DevelopmentThe inventors have demonstrated decreased tumor burden and increased survival in a mouse model of ovarian cancer.
