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 uncontrolled tumor progression and decreased patient survival rate.
Current treatment of tumors with chemotherapy drugs, radiation therapy, targeted kinase inhibition and immunotherapy dominate the oncology pharmacon; yet they fail to sustain control of tumor progression and do not prolong the survival of cancer patients. Although each therapy is associated with specific alterations in the progression of tumors, none of these specifically address the reorganization of the actin cytoskeleton that is a primary factor resulting in tumor resistance. Primary tumors and drug-sensitive tumor cells respond differently than drug-resistant tumor cells to regulation of actin cytoskeletal changes that occur during the progression of cancer.
As tumors become more aggressive, upregulation and activation of cell-surface proteins occurs. These activated cell-surface proteins cause morphological and phenotypical changes in tumors that lead to uncontrolled tumor progression evade the most advanced current cancer therapies.
Oncorx Pharmaceuticals is an early-stage pharmaceutical company developing high-affinity antagonists that selectively target and inhibit the β1 subunit of α3β1 and α5β1integrin that are overexpressed on the surface of therapy-resistant tumor cells. Activation of α3β1 and α5β1 integrin play a critical role in regulating the epithelial-to-mesenchymal transition, anchorage-independent growth, the reorganization of the actin cytoskeleton and cancer stem cells. Reorganization of the actin cytoskeleton also results in the inability of cytotoxic immune cells to lyse tumors, representing a major hurdle in the development of immunotherapies.
Upregulation and activation of cell-surface α5β1integrin also regulates the actin-annexin A5 cytoplasmic complex that restricts membrane translocation of phosphatidylserine and apoptosis of tumor cells. Published studies have shown that blocking activation of α5β1integrin or the actin-annexin A5 cytoplasmic complex restores apoptosis in tumor cells.
Glioma tumors can arise as primary tumors in the brain or from metastatically aggressive carcinoma tumors that have disseminated from their primary site. Regardless of their site of origin, glioma tumors share strikingly similar phenotypical and morphological characteristics to metastatically aggressive carcinoma tumors. These include upregulation and activation of cell-surface α5β1integrin, upregulation of actin-annexin A5 and tumors having exclusive mesenchymal morphologies. Our in-depth proteomic analysis shows that these same characteristics define malignant tumors cells that rapidly disseminate from their primary site to the brain and result in decreased patient survival.
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 brain tumors and aggressive carcinoma tumors that have metastasized to the brain.
Because of their unique re-engineered chemical structure, our proprietary drugs 1) lack the dopaminergic activity and dose-limiting toxicities of similar drugs that cause CNS side effects in patients, and 2) have a lower risk of causing life-threatening cardiac arrhythmias including severe ventricular tachycardia, QTc interval prolongation and torsades de pointes.
Oncorx Pharmaceuticals has completed studies that demonstrate that its lead β1 integrin antagonists 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.
Current treatment of tumors with chemotherapy drugs, radiation therapy, targeted kinase inhibition and immunotherapy dominate the oncology pharmacon;
yet they fail to sustain control of tumor progression and do not prolong the survival of cancer patients.
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