Turning Cold Tumors Hot: Exploring Whether Val-boroPro and Val-boroPro and Doxorubicin Exhibit Synergy in the CT-26 Mouse Tumor Model.
Margosian, Victoria.
2019
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Val-boroPro, a
compound first synthesized in the Bachovchin Lab at Tufts University Sackler School of
Graduate Biomedical Sciences as a dipeptidyl aminopeptidase inhibitor, was found to
stimulate the production of specific cytokines that enhance the immune response to
tumors in a variety of mouse models. However, in these models, a criteria observed to
mediate Val-boroPro's efficacy was the ... read moreimmunogenicity of the cancer cell line targeted
for treatment. In non-antigenically visible cancers, Val-boroPro failed to elicit the
same level of anti-cancer activity, as with those cancers that were known to be
antigenically visible to the hosts immune system. This is feature that is common across
immuno-oncology agents, as only immunogenic cancers elicit the recruitment of both the
innate and the adaptive immune system. In contrast, those cancers that are not
antigenically visible only recruit an innate immune response, which dramatically reduces
their anti-cancer activity. Doxorubicin is an approved chemotherapeutic agent that
interferes with DNA repair mechanisms, and causes cell death by necroptosis. Recent
literature suggests that Doxorubicin is one of several chemotherapeutic agents that is
able to induce immunogenic cell death of tumor cells. This inference followed the
observation that Doxorubicin has greater anti-cancer activity in immune competent
animals than in xenograft models. It is speculated that such a form of cell death might
make the tumor antigenically visible to the hosts immune system. My masters' thesis
hypothesizes that Val-boroPro will synergize with compounds such as doxorubicin that
induce immunogenic cell death. To test this hypothesis, a combination of Val-boroPro and
Doxorubicin were administered to Balb/c mice inoculated with syngeneic tumor model
CT-26, which is a model for colon cancer, and for which Doxorubicin induced immunogenic
cell death has been previously observed. The objective of my project was to determine if
Val-boroPro immune enhancing activity could be harnessed in non-antigenically visible
cancers when it was given with Doxorubicin.
Thesis (M.S.)--Tufts University, 2019.
Submitted to the Dept. of Pharmacology and Drug Development.
Advisors: William Bachovchin, and James Baleja.
Committee: William Bachovchin, and James Baleja.
Keyword: Pharmacology.read less - ID:
- nk322s94s
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