Goal: Overcoming Tumor Resistance and Uncontrolled Tumor Progression

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 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.

Tumor resistance in cancer is the principal driving force behind the ineffectiveness of therapeutic agents and poor patient survival. Tumor resistance and the recurrence of tumors after treatment with anticancer drugs is generally considered to result from cellular activities such as genetic mutations, amplification of genes, cellular switching to alternate oncogenic pathways, and the export of drugs from tumor cells by ATP-driven transporters. Genes encoding cellular signaling molecules and tumor suppressors are tightly regulated in normal cells; however, proteins encoded by these genes acquire transforming functions in malignant tumors due to mutations and overexpression. Although the lack of clinically durable responses and the frequent re-occurrence of invasive tumor cells in cancer patients has been primarily attributed to genetic mutations in protein kinases, epigenetic changes to tumor DNA, and switching to alternate oncogenic pathways during tumor progression, compelling research shows that major changes in the actin cytoskeletal composition, alterations in cell morphology and restricted brain access play critical roles in tumor resistance.

Oncorx Pharmaceuticals has identified therapy-resistant tumor cells that have distinct actin cytoskeletal composition and cell morphology characteristics from therapy-sensitive tumor cells in the majority of solid tumors. Whereas existing therapies are able to regulate the progression of therapy-sensitive tumors, they cannot regulate the progression of therapy-resistant tumors having altered actin cytoskeletal composition and cell morphology characteristics.

Oncorx is developing a novel family of brain penetrating small molecule selective β1 integrin antagonists that disrupt the F-actin cytoskeletal and cell morphology of therapy-resistant tumors.

Uncontrolled Tumor Progression

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.