Kenneth R. Peak Brain and Pituitary Tumor Center: Research Activities
Over the past five years, we have developed a tumor bank from patients with brain tumors. These include large collections of glioblastomas, anaplastic astrocytomas, and pituitary tumors. Each tumor is separated and stored in four different ways. One portion is fixed, waxed and sliced in the form of histopathological slide specimens, which can be analyzed in a number of ways. Another portion is placed in DNA/RNA preservation medium and stored frozen for future studies of the RNA and/or DNA of the cell. A third portion is grown in cell culture medium and the cells are harvested after 3-4 passages in cryoprotectant and stored at 77K. The final portion of the tumor is placed in cancer stem cell medium, and cancer progenitor/stem cells are grown and archived in cryoprotectant. This growing and unique archive will allow researchers here and throughout the world to examine the nature of brain cancer at the genomic and cell physiological levels. It will serve as the basis of high-throughput chemotherapeutic screening. We will examine the efficacy of different drugs, successfully used in other cancers, on primary brain cancers.
We have developed the very first successful selective mitochondrial chemotherapeutic agent for brain cancer. We have designed, synthesized and tested in vitro and in vivo a novel drug family formulated to specifically kill glioma. Gliomas are noted for their upregulation of the mitochondrial enzyme Monoamine oxidase-B, this enzyme converts the uncharged MP-MUS pro-drug into the active, cationic drug P+MUS. P+MUS accumulates in the cells power-house, the mitochondria, destroying its small genome, mitochondrial DNA. The cancer cells attempt to overcome the toxicity by synthesizing more mitochondria, but in doing so increase their levels of Monoamine oxidase-B, and thus make themselves more vulnerable to MP-MUS. Loss of mitochondria, and the release of mitochondrial apoptotic factors cause gliomal cell death.
In collaboration with Jim Tour and the Smalley Institute at Rice University we have made tiny nanosyringes that selectively deliver chemotherapy only to cancer cells. We have been developing two major methods for treating cancer, based on polyethylene glycosylated hydrophilic/hydrophobic carbon cluster (PEG-HCC) nanosyringes. We can fill these syringes with hydrophobic compounds, like the chemotherapeutic drugs docetaxel and vinblastine, and target them to the surface of the tumor by using either antibodies or attaching peptides to the nanosyringes PEG tendrils, which bind to cell surface receptors, found in high levels on the cancer cells. We have demonstrated the ability to specifically target drug filled syringes to the surface antigens of gliomal cells, killing them, and sparing both human astrocytes and neurons.
We have been able to increase the selective toxicity of chemotherapeutic drugs by using the nanosyringes to carry drug pump inhibitors. One of the major reasons for cancer cells drug resistance is that many cancer cells have high levels of drug pumps on their cell surface. These pumps can export chemotherapeutic drugs that diffuse inside the cell back outside.
We fill nanosyringes, targeted to different cell surface antigens, with chemotherapeutic drugs or with inhibitors to the drug pumps which cancer cells use to give themselves resistance to these drugs. Cancer cells, with high levels of the target surface antigens, are covered with nanosyringes that release both drugs and drug pump inhibitors into the cell. Non-cancerous cells typically have low levels of one or more of the selected target antigen, and will receive low, non-toxic, levels of a single chemotherapeutic or drug pump inhibitor. We can therefore achieve very high concentrations of chemotherapeutic drugs inside cancer cells, but very low levels elsewhere, thereby the side effects of chemotherapy while increasing its efficacy.