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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.


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.


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.


Patent
Tau Therapeutics | Date: 2014-01-10

Presented herein are compounds that inhibit T-type Ca^(2+ )channel activity in a cell when the cell membrane potential is about 90 mV. Preferred compounds inhibit T-type Ca^(2+ )channel activity with an IC_(50 )of 10 M or less at a membrane potential of about 90 mV. Preferred compounds show selectivity for inhibiting T-type Ca^(2+ )channel activity at about 90 mV, relative to inhibition of T-type Ca^(2+ )channel activity at about 30 mV to 60 mV, of 10:1 or less. Also provided are methods for identifying compounds that inhibit T-type Ca^(2+ )channel activity in a cell when the cell membrane potential is about 90 mV, and compounds identified by such methods.


Patent
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_(2 )and M phases of the cell cycle to increase the proportion of the eukaryotic cells in the G_(1 )phase, stopping administration of the T type calcium channel inhibitor for a period of time, and administering a dosage selected from the group consisting of a dosage of at least one chemotherapeutic agent, a dosage of radiation, and combinations thereof, to kill the proportion of eukaryotic cells progressing past the G_(1 )phase of the cell cycle after the stopping of the administration of the T type calcium channel inhibitor.


Patent
Tau Therapeutics | Date: 2011-02-28

The present invention provides a method for imaging a disease or condition in a mammal which includes the steps of; administering a therapeutically effective amount of a cell cycle inhibitor to effectively stop proliferation of eukaryotic cells at a cell cycle checkpoint between the G1 and S phase, stopping administration of the cell cycle inhibitor for a period of time, administering a marker to the mammal and imaging the mammal.


News Article | May 28, 2015
Site: www.businesswire.com

CHARLOTTESVILLE, Va.--(BUSINESS WIRE)--Cavion LLC, a pharmaceutical company developing T-type calcium channel inhibitors for the treatment of solid tumors and neurologic diseases, announced today that Matthias Holdhoff, MD, PhD of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins will present preliminary results from an ongoing multi-site National Cancer Institute Adult Brain Tumor Consortium (ABTC) and Cavion-sponsored Phase 1b clinical trial at the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 1. This dose escalation trial, which completed enrollment in November 2014, evaluates the safety and pharmacokinetics of Cavion’s novel cancer drug mibefradil when sequentially administered with temozolomide in patients with recurrent high-grade glioma. Dr. Holdhoff’s poster, entitled “Timed-sequential therapy with mibefradil and temozolomide in patients with recurrent high-grade gliomas: A phase I Adult Brain Tumor Consortium study,” (NCT01480050) concludes that the lack of toxicity and the presence of responses in the selected patient population suggests that the protocol regimen deserves further investigation. Seven ABTC member institutions are participating in the study: Johns Hopkins University, the University of Pennsylvania, Henry Ford Hospital Health System, Emory University, the University of Pittsburgh, the University of Alabama at Birmingham and Wake Forest University. Dr. Holdhoff, who presented the trial design at ASCO in 2013, noted, “I am pleased to update my colleagues on the progress of the trial and our preliminary observations on mibefradil’s safety in patients with recurrent high-grade glioma.” One of those colleagues, Dr. Burt Nabors, Director of the Division of Neuro-oncology at the University of Alabama at Birmingham, said, “As a member of the ABTC, my institution enrolled five patients, two of whom showed strong clinical responses to the treatment regimen. I find our patients’ responses encouraging and look forward to the continued development of T-type calcium channel blockers for the treatment of brain cancer.” “These preliminary results support our belief that our innovative T-type calcium channel blockers provide new opportunities for well-tolerated cancer treatment regimens with increased efficacy to help patients with the most aggressive solid tumor cancers,” stated Cavion President and CEO Andrew Krouse. Cavion is planning to conduct a Phase 2 trial of mibefradil in patients newly diagnosed with glioblastoma. Cavion LLC, founded as Tau Therapeutics LLC, is a privately held clinical stage platform pharmaceutical company creating therapies engaging the T-type calcium channel (Cav3) for the treatment of neurologic and oncologic diseases. The T-type calcium channel is an emerging molecular target for cancer and pain. Cavion is collaborating with the Yale University Comprehensive Cancer Center to co-sponsor a Phase 1 trial (NCT02202993) of the T-type calcium channel blocker mibefradil combined with hypofractionated radiation therapy for the treatment of recurrent glioblastoma multiforme. A multi-site NCI Adult Brain Tumor Consortium-sponsored Phase 1b clinical trial (NCT01480050) of mibefradil administered with temozolomide in brain cancer recently completed enrollment. This press release contains forward-looking statements that are subject to risks and uncertainties, and includes statements that are not historical facts. Actual results could differ significantly from results discussed. Cavion LLC disclaims any intent or obligation to update forward-looking statements, except as required by law.


News Article | April 17, 2015
Site: www.businesswire.com

CHARLOTTESVILLE, Va.--(BUSINESS WIRE)--Cavion LLC, a pharmaceutical company developing T-type calcium channel inhibitors for the treatment of solid tumors and neurologic diseases, announced today that its University of Virginia collaborators Barbara Dziegielewska, Ph.D., and Jaroslaw Dziegielewski, Ph.D., will present data at the Annual Meeting of the American Association for Cancer Research (AACR), the premier cancer research event being held in Philadelphia, Pennsylvania, from April 18-22. Dr. Barbara Dziegielewska will present two posters. One, entitled “Overcoming resistance to anti-EGFR therapy in non-small cell lung cancer with a T-type Ca2+ channels inhibitor,” suggests that a combined treatment of Cavion’s T-type calcium channel inhibitor mibefradil plus tyrosine kinase inhibitors might overcome resistance to anti-epidermal growth factor receptor (EGFR) therapies in non-small cell lung cancer. Her second poster, entitled “T-type Ca2+ channels inhibitors sensitize ovarian cancer to carboplatin through downregulation of survivin gene expression,” shows that administering mibefradil in vitro to ovarian cancer cells results in a simultaneous decrease in expression of the anti-apoptotic gene survivin and increase in apoptosis, which is amplified when mibefradil is combined with carboplatin. This is consistent with observed synergy between mibefradil and carboplatin in ovarian cancer xenografts. These findings provide a rationale for using T-type calcium channel antagonists in combination with standard chemotherapeutics in a clinical trial. Dr. Jaroslaw Dziegielewski’s poster, entitled “Enhancing the Stupp regimen in glioblastoma cancer cells with a T-type calcium channels inhibitor,” demonstrates that inhibiting T-type calcium channels in Glioblastoma multiforme (GBM) affects DNA damage signaling and repair, providing a rational molecular mechanism for the sensitization of GBM to the standard of care Stupp regimen by T-type calcium channel inhibition. “We are honored to have two such capable researchers exploring the impact of T-type calcium channel inhibition across a range of solid tumors. Their studies reinforce our confidence in our innovative and effective therapies for a variety of solid tumor cancers,” said Cavion President and CEO Andrew Krouse. Cavion LLC, founded as Tau Therapeutics LLC, is a privately held clinical stage platform pharmaceutical company creating therapies engaging the T-type calcium channel (Cav3) for the treatment of neurologic and oncologic diseases. The T-type calcium channel is an emerging molecular target for cancer and pain. Cavion is collaborating with the Yale University Comprehensive Cancer Center to co-sponsor a Phase 1 trial of the T-type calcium channel blocker mibefradil combined with hypofractionated radiation therapy; a multi-site NCI Adult Brain Tumor Consortium-sponsored Phase 1b clinical trial of mibefradil administered with temozolomide in brain cancer recently completed enrollment. This press release contains forward-looking statements that are subject to risks and uncertainties, and includes statements that are not historical facts. Actual results could differ significantly from results discussed. Cavion LLC disclaims any intent or obligation to update forward-looking statements, except as required by law.


News Article | May 28, 2015
Site: www.businesswire.com

CHARLOTTESVILLE, Va.--(BUSINESS WIRE)--Cavion LLC, a pharmaceutical company developing T-type calcium channel inhibitors for the treatment of solid tumors and neurologic diseases, announced today that Matthias Holdhoff, MD, PhD of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins will present preliminary results from an ongoing multi-site National Cancer Institute Adult Brain Tumor Consortium (ABTC) and Cavion-sponsored Phase 1b clinical trial at the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 1. This dose escalation trial, which completed enrollment in November 2014, evaluates the safety and pharmacokinetics of Cavion’s novel cancer drug mibefradil when sequentially administered with temozolomide in patients with recurrent high-grade glioma. Dr. Holdhoff’s poster, entitled “Timed-sequential therapy with mibefradil and temozolomide in patients with recurrent high-grade gliomas: A phase I Adult Brain Tumor Consortium study,” (NCT01480050) concludes that the lack of toxicity and the presence of responses in the selected patient population suggests that the protocol regimen deserves further investigation. Seven ABTC member institutions are participating in the study: Johns Hopkins University, the University of Pennsylvania, Henry Ford Hospital Health System, Emory University, the University of Pittsburgh, the University of Alabama at Birmingham and Wake Forest University. Dr. Holdhoff, who presented the trial design at ASCO in 2013, noted, “I am pleased to update my colleagues on the progress of the trial and our preliminary observations on mibefradil’s safety in patients with recurrent high-grade glioma.” One of those colleagues, Dr. Burt Nabors, Director of the Division of Neuro-oncology at the University of Alabama at Birmingham, said, “As a member of the ABTC, my institution enrolled five patients, two of whom showed strong clinical responses to the treatment regimen. I find our patients’ responses encouraging and look forward to the continued development of T-type calcium channel blockers for the treatment of brain cancer.” “These preliminary results support our belief that our innovative T-type calcium channel blockers provide new opportunities for well-tolerated cancer treatment regimens with increased efficacy to help patients with the most aggressive solid tumor cancers,” stated Cavion President and CEO Andrew Krouse. Cavion is planning to conduct a Phase 2 trial of mibefradil in patients newly diagnosed with glioblastoma. Cavion LLC, founded as Tau Therapeutics LLC, is a privately held clinical stage platform pharmaceutical company creating therapies engaging the T-type calcium channel (Cav3) for the treatment of neurologic and oncologic diseases. The T-type calcium channel is an emerging molecular target for cancer and pain. Cavion is collaborating with the Yale University Comprehensive Cancer Center to co-sponsor a Phase 1 trial (NCT02202993) of the T-type calcium channel blocker mibefradil combined with hypofractionated radiation therapy for the treatment of recurrent glioblastoma multiforme. A multi-site NCI Adult Brain Tumor Consortium-sponsored Phase 1b clinical trial (NCT01480050) of mibefradil administered with temozolomide in brain cancer recently completed enrollment. This press release contains forward-looking statements that are subject to risks and uncertainties, and includes statements that are not historical facts. Actual results could differ significantly from results discussed. Cavion LLC disclaims any intent or obligation to update forward-looking statements, except as required by law.

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