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Therapeutic disruption of Connexin mediated microtubule regulation to target glioblastoma cancer stem cells

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41CA217503-01
Agency Tracking Number: R41CA217503
Amount: $224,999.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 100
Solicitation Number: PA16-303
Solicitation Year: 2016
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-09-01
Award End Date (Contract End Date): 2019-08-31
Small Business Information
Roanoke, VA 24016-5103
United States
DUNS: 080205668
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (843) 860-8372
Business Contact
Phone: (415) 845-2992
Research Institution
BLACKSBURG, VA 24061-6100
United States

 Nonprofit College or University

Project Summary
Glioblastoma GBM is one of the most lethal incurable human diseases Even with aggressive therapies
including surgical resection followed by radiotherapy and chemotherapy using temozolomide TMZ the median
survival for GBM patients is only months In fact GBM cancer cells are highly infiltrative and comprise a sub
population of glioma stem cells GSCs with tumorigenic properties regulated by the tumor microenvironment
and often resistant to chemotherapy and irradiation treatments The remaining GSCs can then enter an active
state of self renewal and asymmetric division that recapitulates the heterogeneous tumor As a result all treated
GBM patients will experience tumor recurrence and subsequent surgeries and toxic radiotherapy and
chemotherapy regimens are harmful for the patient and often remain insufficient There is therefore an urgent
need for new therapeutic drug to target GSCs and treat this devastating disease Glioblastoma resistance to
TMZ correlates with the expression of the gap junction protein Connexin Cx a protein which enables
communication between cells and increased levels of Cx are observed in GSCs The function of Cx is not
limited to forming channels for the passage of ions and small molecules between cells but also participates in
cell proliferation migration and apoptosis Therefore targeting Cx activity holds promise to treat GBM and
prevent tumor recurrence In this proposed research we use a novel Cx mimetic peptide named JM
juxtamembrane that encompasses the microtubule binding sequence of Cx Our preliminary data show
that JM alters Cx binding to microtubule decreases the formation of Cx gap junctions and inhibits cell
cell communication in GSCs Most importantly we reveal the therapeutic potential of JM in decreasing GSC
survival in vitro and in vivo With the goal of developing a new therapy based upon JM to target GSCs in GBM
our overall objective is to generate JM loaded polyanhydride biodegradable nanoparticles JM NPs for
sustained delivery of JM to GSCs We will use high resolution microscopy techniques including stochastic
optical reconstruction microscopy STORM and biochemistry assays to analyze the effect of JM NPs in GSCs
derived from human primary GBM cells freshly isolated from dissected patient tumor Finally we will assess the
therapeutic effect of JM NPs on GSCs ex vivo using a three dimensional patient GBM derived organoid model
and in vivo using an orthotopic GBM mouse model These results will validate the potent effect of JM peptide
for treatment of high Cx chemoresistant GSCs and present a therapeutic opportunity to prevent GBM tumor
recurrence The proposed research is significant because this innovative approach will not only allow us to
develop novel therapies for lethal GBM but also will lay foundation on potential clinical trials in newly diagnosed
GBM patients in the near future Finally our new JM loaded nanoparticles may be scalable to other CNS
diseases that could benefit from targeting Cx microtubule interaction Project Narrative
Glioblastoma is the most aggressive type of brain tumor and one of the most deadly diseases with no efficient
therapy to cure it The proposed research aims at developing a new therapeutic strategy to target tumor
initiating cells in glioblastoma Therefore this work will have important impact on therapeutic intervention for
glioblastoma and is relevant to public health and NIH s mission

* Information listed above is at the time of submission. *

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