Restoring Tumor Suppressors

​​​​​​​​​​​​​​​OncoRx Pharmaceuticals is an early-stage pharmaceutical company discovering and developing targeted therapies that control the progression of invasive malignant cancer.  OncoRx has identified and tested drugs that markedly alter the sustained directional mobility, the uncontrolled cell cycle, and t​​he unrestrained growth and proliferation of intrinsically and acquired therapy-resistant tumors. Unlike non-aggressive primary tumors, the growth, progression and invasiveness of therapy-resistant tumors are not effectively controlled with currently available cancer therapies such as chemotherapy, radiotherapy and the new targeted kinase inhibitors.

OncoRx is developing proprietary cancer drugs that can target and restore tumor suppressor activity in therapy-resistant tumor cells. These drugs are analogs of the phenothiazine drug thioridazine; a drug that has demonstrated unequaled effectiveness against therapy-resistant tumors and self-renewing cancer stem cells. Unfortunately, thioridazine has been removed from the worldwide market over concerns of life-threatening cardiotoxicity. OncoRx is also developing novel nanodrug carriers that can transport small-molecule drugs into therapy-resistant mesenchymal cells. Both of these development platforms are focused on restoring tumor suppressors so that drug-resistant tumors can self-regulate uncontrolled proliferation, tumor invasion and a normal cell cycle.

Targeting Metastasizing Tumors  

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​​Transformation of primary, drug-sensitive tumor cells into highly aggressive malignant tumor cells is accompanied by the remodelling of the tumor cell surface by upregulation of the P-glycoprotein (P-gp) drug efflux transporter. Studies have shown that P-gp expression is markedly increased in invasive carcinoma tissue, lymph nodes and drug-resistant mesenchymal cells as tumors metastasize.  Known primarily as a drug efflux transporter, P-gp has also demonstrated control over oncogenic signaling and plays a critical role in the proliferation of therapy-resistant tumors and self-renewing cancer stem cells.Tricyclic phenothiazines  have shown a high affinity toward the P-gp transporter, marked inhibition of P-gp drug efflux activity, marked inhibition of tumor growth and cell invasion, and the ability to induce cell-cycle arrest and apoptosis in drug-resistant tumors.​​  The effectiveness of tricyclic phenothiazines to reduce tumor metastases in xenograft animal studies has been reported for a variety of cancer types including malignant melanoma, glioblastoma, lung cancer and ovarian cancer. 

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​​​​​​​OncoRx is developing high-affinity tricyclic phenothiazine analogs that selectively target glycoproteins such as P-gp and the β1 subunit of α4β1 integrin that are overexpressed on the surface of therapy-resistant tumors. These drugs can restore the activity of downregulated tumor suppressors and disrupt the sustained directional migration of tumor  cells. These are hallmarks of malignant tumor proliferation and metastasis.  Tricyclic phenothiazines have been reported to induce apoptosis in tumor cells and  markedly inhibit tumor growth in both subcutaneous and orthotopic mouse xenografts.

Unlike thioridazine and structurally similar phenothiazines, our proprietary drugs lack the dopaminergic activity and dose-limiting toxicities that cause CNS side effects in patients. Unlike thioridazine and structurally related tricyclic drugs, our proprietary drugs have a lower risk of causing life-threatening cardiotoxicity. Unlike structurally modified tricyclic drugs, our proprietary drugs retain the essential structural elements required for oncolytic activity against therapy-resistant tumors. Unlike current drug therapies that have limited access to the brain, our proprietary phenothiazine drugs cross the blood-brain-barrier (BBB) to gain unfettered access to intractable primary and metastatic malignant brain tumors. ​​