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Charlottesville, VA, United States

Keir S.T.,Duke University | Friedman H.S.,Duke University | Reardon D.A.,Duke University | Bigner D.D.,Duke University | Gray L.A.,Tau Therapeutics
Journal of Neuro-Oncology | Year: 2013

Glioblastoma multiforme (GBM) is a devastating disease with a dismal prognosis and a very limited response to treatment. The current standard of care for GBM usually consists of surgery, radiation and chemotherapy with the alkylating agent temozolomide, although resistance to this drug is common. The predominant mechanism of action of temozolomide is methylation of guanine residues although this can be reversed by methylguanine methyltransferase (MGMT) as well as other DNA repair systems. The presence of methylguanine causes abortive DNA synthesis with subsequent apoptosis. This suggests that the closer a particular cell is to S phase when it is exposed to temozolomide the more likely it is to die since repair enzymes will have had less time to reverse the damage. T type calcium channel inhibitors can stop the entry of extracellular calcium that is necessary for transit past the G1/S boundary. As a result, T type calcium channel blockers can slow the growth of cancer cells, but do not generally kill them. Though slowing the growth of cancer cells is important in its own right, it also provides a therapeutic strategy in which a T type channel blocker is administered then withdrawn followed by the administration of temozolomide. We show here that imposing this cell cycle restriction increases the efficacy of subsequently administered temozolomide in immunodeficient mice bearing various human GBM xenograft lines. We also present data that MGMT expressing GBM tumors, which are temozolomide resistant, may be rendered more sensitive by this strategy. © 2012 Springer Science+Business Media New York.

Gray L.S.,Tau Therapeutics | Schiff D.,University of Virginia | Macdonald T.L.,University of Virginia
Expert Review of Anticancer Therapy | Year: 2013

Ca2+ influx at critical points in the cell cycle is required for proliferation. This requirement is so ubiquitous that its occurrence is often treated as background noise. Yet without it, cells stop dividing, suggesting an obvious and potentially effective way to treat cancer. To control proliferation by controlling Ca2+ influx requires that the mechanism be elucidated, but this field of study has been filled with controversy and devoid of therapeutic utility. In this study, the authors present a model for the regulation of Ca2+ influx at the G1/S restriction point in cancer and stem cells that is simple, cohesive and, we believe, reasonably complete. The model illustrates the essential role of T-type Ca2+ channels in mediating influx and points clearly to the therapeutic strategies that have recently entered clinical trials. © 2013 2013 Expert Reviews Ltd.

Valerie N.C.K.,University of Virginia | Dziegielewska B.,University of Virginia | Hosing A.S.,University of Virginia | Augustin E.,Technical University of Gdansk | And 4 more authors.
Biochemical Pharmacology | Year: 2013

Glioblastoma multiforme (GBM) are brain tumors that are exceptionally resistant to both radio- and chemotherapy regimens and novel approaches to treatment are needed. T-type calcium channels are one type of low voltage-gated channel (LVCC) involved in embryonic cell proliferation and differentiation; however they are often over-expressed in tumors, including GBM. In this study, we found that inhibition of T-type Ca2+ channels in GBM cells significantly reduced their survival and resistance to therapy. Moreover, either T-type selective antagonists, such as mibefradil, or siRNA-mediated knockdown of the T-type channel alpha subunits not only reduced cell viability and clonogenic potential, but also induced apoptosis. In response to channel blockade or ablation, we observed reduced phosphorylation of Akt and Rictor, suggesting inhibition of the mTORC2/Akt pathway. This was followed by reduction in phosphorylation of anti-apoptotic Bad and caspases activation. The apoptotic response was specific for T-type Ca2+ channels, as inhibition of L-type Ca2+ channels did not induce similar effects. Our results implicate T-type Ca2+ channels as distinct entities for survival signaling in GBM cells and suggest that they are a novel molecular target for tumor therapy. © 2012 Elsevier Inc.

Dziegielewska B.,University of Virginia | Gray L.S.,Tau Therapeutics | Dziegielewski J.,University of Virginia
Pflugers Archiv European Journal of Physiology | Year: 2014

T-type calcium channels are involved in a multitude of cellular processes, both physiological and pathological, including cancer. T-type channels are also often aberrantly expressed in different human cancers and participate in the regulation of cell cycle progression, proliferation, migration, and survival. Here, we review the recent literature and discuss the controversies, supporting the role of T-type Ca2+ channels in cancer cells and the proposed use of channels blockers as anticancer agents. A growing number of reports show that pharmacological inhibition or RNAi-mediated downregulation of T-type channels leads to inhibition of cancer cell proliferation and increased cancer cell death. In addition to a single agent activity, experimental results demonstrate that T-type channel blockers enhance the anticancer effects of conventional radio- and chemotherapy. At present, the detailed biological mechanism(s) underlying the anticancer activity of these channel blockers is not fully understood. Recent findings and ideas summarized here identify T-type Ca2+ channels as a molecular target for anticancer therapy and offer new directions for the design of novel therapeutic strategies employing channels blockers. Physiological relevance: T-type calcium channels are often aberrantly expressed or deregulated in cancer cells, supporting their proliferation, survival, and resistance to treatment; therefore, T-type Ca2+ channels could be attractive molecular targets for anticancer therapy. © 2014 Springer-Verlag.

Tau Therapeutics | Date: 2010-06-04

The present invention provides a method for treating a disease or condition in a mammal which comprises the steps of; administering a therapeutically effective amount of a T type calcium channel inhibitor to effectively slow or stop progression of eukaryotic cells through the S, G

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