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A natural, physiological wall called the blood-brain barrier (BBB) has been one of the most difficult challenges facing specialists who are trying to deliver therapeutic drugs to brain tumors. Although the portion of the BBB near brain tumors is different from the BBB, the blood-brain tumor barrier also effectively prevents the delivery of anti-cancer drugs to tumor.
Scientists at the Institute discovered that a naturally occurring peptide called bradykinin, as well as nitric oxide-generating compounds, phosphodiesterase 5 inhibitors, and potassium channel activators, can temporarily open this barrier. Bradykinin actually increases anti-cancer drug delivery into a tumor by more than 1,000 percent, without exposing healthy brain tissue, however it was found recently that bradykinin causes patient hypotension and the BBB opening effect is short. PDE5 inhibitors have an advantage over bradykinin's side effects since the inhibitors help deliver small drugs and high molecular weight therapeutics such as monoclonal antibody and nano-molecules into the brain. This type of drug delivery into the brain is impossible without the co-treatment of PDE5 inhibitors.
In our ongoing efforts to fine-tune these treatments and direct more chemical drugs, biotherapeutics or even genetically engineered cancer-fighting viruses into tumors, our researchers are looking at the molecular and enzymatic steps that enable the blood-brain barrier opening process to occur. We recently found, for example, a protein convergence point where several activities take place to regulate tumor barrier permeability.
Through this research, we look forward to improving drug delivery for brain tumors, other kinds of cancers and a variety of neurologic disorders, including strokes, CNS trauma, Alzheimer's disease, Parkinson's disease and multiple sclerosis.
The research of Principle Investigator, Dr. Keith Black, has long been is funded by the NIH to investigate biochemical modulation of the BBB for enhanced delivery of chemotherapeutic drugs to brain tumors. The Co-Principle Investigator, Dr. Julia Ljubimova joined the research group in August 2008 with expertise in the fields of drug delivery, cancer molecular markers and nanomedicine. The research groups uses experimental brain tumor rodent models that incorporate surgical procedures and molecular techniques to develop therapeutic strategies for effective delivery of anti-cancer drugs for the treatment of brain tumors. Further clinical studies are being started on the pre-clinical findings. These translational research studies provides training to pre-doctoral student and post-doctoral research in the areas of cellular and molecular biology, microsurgical techniques, and pre-clinical investigation leading to human clinical trials. Thus, with emphasis on translational research at the Maxine Dunitz Neurosurgical Institute, there is a unique and rare opportunity for students to learn, train and experience benchtop to bedside biomedical research at a medical center.
Black KL, Yin D, Ong JM, Hu J, Konda BM, Wang X, Ko MK, Bayan JA, Sacapano MR, Espinoza A, Irvin DK, Shu Y. PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model. Brain Res. 2008,1230:290-302.
Hu J, Yuan X, Ko MK, Yin D, Sacapano MR, Wang X, Konda BM, Espinoza A, Prosolovich K, Ong JM, Irvin D, Black KL. 2007. Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model. Mol Cancer. 6:22.
Yin D, Kawabata H, Tcherniamtchouk O, Huynh T, Black KL, Koeffler HP. 2007. Glioblastoma multiforme cells: Expression of erythropoietin receptor and response to erythropoietin. Int J Oncol. 31:1193-8.
Yin D, Ong JM, Hu J, Desmond JC, Kawamata N, Konda BM, Black KL, Koeffler HP. 2007. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor: effects on gene expression and growth of glioma cells in vitro and in vivo. Clin Cancer Res. 13:1045-52.
Badruddoja MA, Black KL. 2006. Improving the delivery of therapeutic agents to CNS neoplasms: a clinical review. Front Biosci. 11:1466-78.
Yin, D., H. Zhou, T. Kumagai, G. Liu, J. M. Ong, K. L. Black, and H. P. Koeffler. 2005. Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). Oncogene 24: 344-54.
Xiao-xue Z., K. L. Black, J. M. Ong, O. Bogler, Y. Zhai, and C. J. Wheeler. 2005. T cell activity in glioma chemoresponsiveness and genetics. Gene Ther Mol Biol Vol 9, 401-416, 2005
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