Targeted nanoTherapy to Precision Oncology Platform (TnT POP) for Veterans

Jesse Brown Va Medical Center, Chicago IL

Investigators

Abstract

PROJECT SUMMARY The Veterans of the Armed Services are disproportionately exposed to toxins that can increase their risk of developing cancer. Many of these cancers are, or become, highly resistant to common therapies, like chemotherapy and radiation (XRT), which leads to high morbidity and mortality. New precision diagnostics and treatments are required. Our research group discovered that seemingly disparate cancers, arising from different cell and tissue types (e.g., lymphomas and kidney cancer) can be unified by a common phenotype. This is especially true for cancers – like kidney cancer – resistant to common therapeutic modalities, like chemotherapy and radiation (XRT). We discovered a metabolic-redox phenotype in some cancers defined by cholesterol uptake and redox dependence. This cancer phenotype was identified because of a class of targeted and functional lipoprotein-like nanoparticles, called high-density lipoprotein-like nanoparticles (HDL NP), that we invented. The HDL NP, like natural cholesterol-rich HDL (crHDL), binds with high affinity to a cell surface receptor called scavenger receptor class B type I (SR-B1). However, we engineered the HDL NP as a cholesterol-poor ligand for SR-B1, which outcompetes the crHDL ligand for SR-B1 binding. As a result, HDL NP powerfully modulates cell membrane and cell cholesterol balance, which results in powerful therapy to kill cancer cells. Further, we found that cancer cells sensitive to HDL NP are also highly dependent upon the function of a lipid antioxidant enzyme called glutathione peroxidase 4 (GPX4) responsible for repairing oxidized phospholipids in the cell membrane. This function of GPX4 is particularly responsible for rendering cancer cells resistant to otherwise toxic lipid reactive oxygen species (L-ROS) generated by chemotherapy and XRT. HDL NP treatment abolishes the expression of GPX4. Accordingly, HDL NP treatment, by targeting cancers defined by their cholesterol uptake (SR-B1) and redox dependence (GPX4), powerfully induces an iron-dependent mechanism of cell death called ferroptosis that results from the catastrophic oxidation and destruction of the cancer cell membrane. Accordingly, the metabolic-redox cancer phenotype enables precision diagnosis using the metabolic (SR-B1) and redox (GPX4) biomarkers. Also, the HDL NP provides a potent drug platform to fully understand the mechanism of cell death in these cancers and novel treatment modalities. We will address these goals by exploring three Aims: 1) Identify the physicochemical properties of HDL NPs that exact SR-B1 binding, reduce GPX4, and induce ferroptosis. 2) Discover the metabolic-redox mechanism(s) through which HDL NP binding SR-B1 results in drastic reduction in GPX4 and ferroptosis. 3) Define HDL NP therapy as a powerful, targeted agent to sensitize tumors to radiation therapy (XRT) that largely depends upon generating lethal ROS in tumor cells and tissue. Successful completion of the proposed studies will identify a precision diagnostic and treatment paradigm for Veterans with kidney cancer.