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Treating melanoma in an experimental system by targeting glutamatergic signaling and PD-1 inhibition

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TitleInfo
Title
Treating melanoma in an experimental system by targeting glutamatergic signaling and PD-1 inhibition
Name (type = personal)
NamePart (type = family)
Robinson
NamePart (type = given)
Ann K.
NamePart (type = date)
1991-
DisplayForm
Ann K. Robinson
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Minden
NamePart (type = given)
Audrey
DisplayForm
Audrey Minden
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Chen
NamePart (type = given)
Suzie
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Suzie Chen
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Gunderson
NamePart (type = given)
Samuel
DisplayForm
Samuel Gunderson
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
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school
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Text
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theses
OriginInfo
DateCreated (qualifier = exact)
2017
DateOther (qualifier = exact); (type = degree)
2017-10
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2017
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Melanoma is the most dangerous type of skin cancer due to the frequency of metastasis and resistance to therapies, including radiation, traditional chemotherapies, and targeted therapies. Drug resistance and immune evasion are two issues currently gaining attention in the areas of melanoma research and treatment. To combat drug resistance, various combination treatment strategies are under investigation. Immune checkpoint blockade, a popular area of immunotherapy, aims to harness a patient’s cytotoxic T cell response to combat tumor growth. Previously, our group identified the ectopic expression of a normal neuronal receptor, metabotropic glutamate receptor 1 (mGluR1) in the etiology of melanoma development and pathogenesis. When aberrantly expressed in melanocytes, mGluR1 activates two of the most commonly dysregulated signaling cascades, MAPK and P13K/AKT pathways that promote cellular proliferation while inhibiting apoptosis. To interrupt signaling through mGluR1, we took advantage of the anti-glutamatergic activity of riluzole. Riluzole is an FDA approved drug for the treatment of amyotrophic lateral sclerosis (ALS). In the current study, in addition to using riluzole as an antagonist to mGluR1, we also used a newly developed prodrug for riluzole, FC4157. Tumor biopsies from patients who participated in our Phase 0 and 2 clinical trials with riluzole suggest those who benefit from the drug have suppression of angiogenesis and increased leukocyte numbers at the tumor-stroma interface. Based on these observations, we began to test in a preclinical experimental model system, the efficacy of combining either riluzole or FC4157 with PD-1 checkpoint blockade. We observed a significant reduction in tumor volumes in animals receiving either riluzole or FC4157 in combination with PD-1 blockade, as compared to vehicle or monotherapy treated groups. Western blot analysis on excised tumor lysates showed evidence of alterations to PD-1 ligand and DNA damage markers, suggesting tumors from animals receiving combination therapies may be less likely to evade cytotoxic T cell responses and may respond better to anti-PD-1 treatment. Finally, ELISA array data from tumor tissues, splenic tissues, and serum samples indicate a dynamic, but ultimately favorable tumor microenvironment for an anti-tumor immune response.
Subject (authority = RUETD)
Topic
Microbiology and Molecular Genetics
Subject (authority = ETD-LCSH)
Topic
Melanoma--Treatment
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_8373
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (x, 78 p. : ill.)
Note (type = degree)
M.S.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Ann K. Robinson
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3NP27K5
Genre (authority = ExL-Esploro)
ETD graduate
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Robinson
GivenName
Ann
MiddleName
K.
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2017-09-21 00:13:16
AssociatedEntity
Name
Ann Robinson
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Technical

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DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2017-09-26T14:47:54
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2017-09-26T14:47:54
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