Oncorx Pharmaceuticals has developed high-affinity tricyclic phenothiazine drugs that selectively target the P-glycoprotein/CD44 complex and the β1 subunit of α4β1 integrin that are overexpressed on the surface of therapy-resistant tumors. The expression of P-glycoprotein on the therapy-resistant cell surface not only restricts access of many drugs into the altered tumor cell; it's expression creates an anchoring scaffold for a new dominant signaling pathway through α4β1 integrin. Activation of α4β1 integrin plays a crucial role in regulating the epithelial-to-mesenchymal transition, anchorage-independent growth, the reorganization of the actin cytoskeleton and cancer stem cells. It has been reported in several aggressive cancer types that the α4β1/FAK/STAT3 becomes dominant in the control of STAT3 activation in therapy-resistant tumor cells. These include both solid tumors (carcinomas) and hematopoietic tumors (leukemias); mesenchymal anchorage-independent (anoikis-resistant) tumors as well as anchorage-dependent epithelia tumors; and self-renewing cancer stem cells.
In addition, phenothiazines have been shown to reactivate the silenced phosphatase activity of the tumor suppressor PTEN in therapy-resistant tumors through upregulation of EGR1 expression. EGR1 expression is regulated in therapy-sensitive tumors by epidermal growth factor (EGF); however, EGR1 expression is mainly regulated by integrins in therapy-resistant tumors. Loss of PTEN expression results in dysregulation of PI3K/AKT signaling pathway, dysregulation of chemokine-mediated signaling, and enhancement of migration and invasion. In addition to its well-known lipid phosphatase activity and its role in the PI3K/AKT pathway, PTEN possesses protein phosphatase activity that plays an important role in the α4β1/FAK/STAT3 pathway (see diagram above).
Our high-affinity phenothiazine drugs have multiple effects in treating resistant tumors; a) they inhibit the activation of STAT3 in cooperation with the P-gp anchored α4β1; b) they restore PTEN protein phosphatase activity to its normal suppressor function; and C) they reduce the self-renewing cancer stem cell populations in a number of resistant tumor cells, including breast cancer cell lines SUM159, SUM149, MCF7 and MDA-MB-231; and melanoma cell lines MM603, SkMel19, SkMel28, SkMel29, SkMel94, and SkMel173 .
Thioridazine, the most potent phenothiazine in tumor regulation, is a tricyclic phenothiazine drug that is transformed to highly reactive quinoneimine metabolites after administration by myeloperoxidase and CYP4502D6. Although published studies have shown that thioridazine is one of the most effective compounds for treating resistance tumors; its off-target side effects have prevented successful development of a clinically effective drug product. The most important of these is its well-known QT prolongation; caused by its inhibition of the hERG K+ channels and the highly reactive quinoneimine metabolites.
Quinoneimine cardiotoxicity is not manifest an all patients; it's risk increases in the presence of peroxidase activation. Not surprisingly, the level of myeloperoxidase in cancer patients has been shown to be markedly upregulated; with up to an 8-fold increase over that in normal serum. These reactive quinoneimine metabolites react with molecular oxygen with marked efficiency to generate singlet oxygen (1O2); which then inhibits cardiac Na+, K+ ATPase in the low micromolar concentration range. Numerous scientific studies have shown that inhibition of cardiac Na+, K+ ATPase with thioridazine and related phenothiazines causes dysregulation of K+, severe ventricular tachycardia, QT prolongation, 3rd degree AV block and torsade de pointes.
Oncorx has developed a first-in-class family of phenothiazine drugs that interact minimally with the hERG K+ channels and are low risk for QT prolongation caused by these channels. Our drugs have also been reengineered to preclude formation of highly reactive quinoneimine metabolites and singlet oxygen (1O2).