Goal: Overcoming Tumor Resistance

Tumor Resistance

Currently, the progression of primary tumors is an objective measure primarily based upon the size and shape of a tumor after therapy and expressed in terms of partial or complete remission. Partial and complete remission of primary tumors by radiation, targeted kinase inhibitors, and immunotherapies has been achieved; however, their success is short-lived. As tumor cells disseminate beyond their primary tumor site, migrate through the bloodstream and spread to distant metastatic sites, the proteins on their cell surface undergo major transformations that cause the tumor cells to become resistant to conventional treatments. As tumors progress, genes for critical tumor suppressors are silenced and cell-surface targets become unresponsive to immunologically-directed therapies. The inability to treat this resistance clearly translates into decreased patient survival rate

Oncorx Pharmaceuticals has spent the past decade understanding the causes of tumor resistance and developing therapies to mitigate its uncontrolled progression. Our initial drug products are Orphan Drugs for the treatment of intractable, high-grade gliomas in the brain. Diffuse Intrinsic Pontine Glioma (DIPG) and glioblastoma multiforme (GBM) are two primary brain cancers that have an extraordinarily low patient survival rate. There is currently no effective therapy to treat or control either of these aggressive tumors. Our follow-on indications for the treatment of tumors that readily metastasize to the brain include malignant melanoma, lung cancer, colon cancer, pancreatic cancer, ovarian cancer and estrogen-negative breast cancer.

Uncontrolled Tumor Progression

Cell-surface Remodeling

Oncorx Pharmaceuticals is an early-stage pharmaceutical company developing 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. 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. 

  

Activation of the P-glycoprotein/CD44 complex provides a scaffold anchored on the cell surface of resistant tumors that facilitates the interaction of CXCR4, α4β1, FAK, Rho kinase and STAT3. The remodeling of the tumor cell surface during the epithelial-to-mesenchymal transition a) changes the therapy-resistant tumor's interaction with its microenvironment; b) promotes sustained directional migration through extensive cytoskeletal reorganization; and c) creates new dominant tumor-promoting signaling pathways that are not found in drug-sensitive epithelial cells.

  

Because therapy-sensitive tumor cells lose or become deficient in PTEN protein phosphorylase activity as they disseminate beyond the primary tumor site, the activation of STAT3 to P-STAT3 goes unchecked in therapy-resistant tumor cells. Phenothiazine drugs can restore the activity of downregulated tumor suppressors such as PTEN, inhibit the phosphorylation and activation of STAT3, and disrupt the sustained directional migration of tumor cells in therapy-resistant tumor cells for a variety of cancer types including malignant melanoma (with BRAFV600E mutation), glioblastoma, triple-negative breast cancer, lung cancer, colon cancer and ovarian cancer. Because drug-sensitive tumor cells become unresponsive to cytokine or growth factor therapy control of STAT3 activation, EGFR/STAT3 and IL-6R/STAT3 therapy are of little value in treating therapy-resistant tumor cells. It has been reported in several aggressive cancers that the α4β1/FAK/STAT3 becomes dominant in the control of STAT3 activation in therapy-resistant tumor cells. Our high-affinity phenothiazine drugs have a dual role in treating resistant tumors; a) they inhibit the activation of STAT3 by α4β1; and b) they restore PTEN protein phosphatase activity to its normal suppressor function. ​

  

Unlike current drug therapies that have limited access to the brain, our proprietary drugs readily cross the blood-brain-barrier (BBB) to gain unfettered access to intractable primary and metastatic malignant brain tumors. Unlike structurally similar phenothiazines, our proprietary drugs lack the dopaminergic activity and dose-limiting toxicities that cause CNS side effects in patients. Because of their unique re-engineered chemical structure, our proprietary drugs have a lower risk of causing life-threatening cardiac arrhythmias including severe ventricular tachycardia, QTc interval prolongation and torsades de pointes


The Company has completed studies that demonstrate that its lead thioridazine-like drugs are cytotoxic against multiple drug-resistant tumors and multiple types of self-renewing cancer stem cells at clinically-relevant concentrations. Our technology is protected by trade secrets and patents. Our proprietary drugs are protected by patents issued in the United States and several European countries.