TARGETED DEGRADATION OF THE MYC ONCOGENE USING PP2AB56ALPHASELECTIVE SMALL MOLECULE MODULATORS OF PROTEINPHOSPHATASE 2A AS A THERAPEUTIC STRATEGY FOR TREATING MYCDRIVENCANCERS

TARGETED DEGRADATION OF THE MYC ONCOGENE USING PP2AB56ALPHASELECTIVE SMALL MOLECULE MODULATORS OF PROTEINPHOSPHATASE 2A AS A THERAPEUTIC STRATEGY FOR TREATING MYCDRIVENCANCERS

Bibliographic Details
Main Author: Farrington, Caroline Cain
Language:English
Published: Case Western Reserve University School of Graduate Studies / OhioLINK 2020
Subjects:
Biomedical Research
Pharmacology
Burkitt Lymphoma
non-small cell lung cancer
small molecule activator of PP2A
SMAP
anticancer drug
Myc
c-Myc
breast cancer
protein phosphatase 2
PP2A
protein degradation
oncogene
small molecule
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=case1579905487094187
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-case15799054870941872021-08-03T07:13:46Z TARGETED DEGRADATION OF THE MYC ONCOGENE USING PP2AB56ALPHASELECTIVE SMALL MOLECULE MODULATORS OF PROTEINPHOSPHATASE 2A AS A THERAPEUTIC STRATEGY FOR TREATING MYCDRIVENCANCERS Farrington, Caroline Cain Biomedical Research Pharmacology Burkitt Lymphoma non-small cell lung cancer small molecule activator of PP2A SMAP anticancer drug Myc c-Myc breast cancer protein phosphatase 2 PP2A protein degradation oncogene small molecule A governing principle of cancer development is defined by a coordinate gain of oncogenic function and loss of tumor suppressor activity. To fully reverse this pathogenic process, one would want to simultaneously inhibit oncogene activity while reengaging tumor suppressor function. However, the majority of targeted therapies are directed at modulating the oncogenic gain with few therapies directed at the critical tumor suppressor proteins. This is based upon the dogma that, in a cell, it is easier to turn something off than to turn something back on. Indeed, activation of tumor suppressors using pharmaceutically tractable approaches have proven to be challenging. Yet, efforts persist to develop activators of tumor suppressor proteins. One that stands out as a therapeutic target is Protein Phosphatase 2A (PP2A). PP2A is a serine/threonine phosphatase involved in the regulation of many cellular processes and is genetically altered or functionally inactivated in many cancers highlighting its central role in cancer pathogenesis. One of the best-defined substrates of PP2A is the transcription factor c-MYC (MYC). MYC, a well-described oncogene, is activated through both genetic amplification and stabilizing post-translational modifications. Cancers associated with high MYC expression are generally more aggressive. However, MYC has remained an elusive drug target as it lacks targetable drug pockets. MYC is rapidly degraded and its activity is inhibited by active PP2A. Thus, PP2A reactivation is a proposed strategy for the treatment of MYC driven cancers. Small Molecule Activators of PP2A (SMAPs) have been recently described for their potent anti-cancer activity which is dependent upon their ability to activate PP2A, reengaging its tumor suppressor activity. This research demonstrates that activation of PP2A by SMAPs leads to MYC degradation resulting in the inhibition of cancer growth in both cellular and in vivo model systems. Biochemical and genetic tools are used to demonstrate that this anti-cancer activity is directly related to the degradation of MYC through the modulation of PP2A activity. In summary, the activation of tumor suppressor PP2A leads to the inhibition of MYC, and establishes that SMAP mediated activation of PP2A is a novel approach that could be used for the treatment of MYC driven cancers. 2020-05-29 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1579905487094187 http://rave.ohiolink.edu/etdc/view?acc_num=case1579905487094187 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Biomedical Research
Pharmacology
Burkitt Lymphoma
non-small cell lung cancer
small molecule activator of PP2A
SMAP
anticancer drug
Myc
c-Myc
breast cancer
protein phosphatase 2
PP2A
protein degradation
oncogene
small molecule
spellingShingle Biomedical Research
Pharmacology
Burkitt Lymphoma
non-small cell lung cancer
small molecule activator of PP2A
SMAP
anticancer drug
Myc
c-Myc
breast cancer
protein phosphatase 2
PP2A
protein degradation
oncogene
small molecule
Farrington, Caroline Cain
TARGETED DEGRADATION OF THE MYC ONCOGENE USING PP2AB56ALPHASELECTIVE SMALL MOLECULE MODULATORS OF PROTEINPHOSPHATASE 2A AS A THERAPEUTIC STRATEGY FOR TREATING MYCDRIVENCANCERS
author Farrington, Caroline Cain
author_facet Farrington, Caroline Cain
author_sort Farrington, Caroline Cain
title TARGETED DEGRADATION OF THE MYC ONCOGENE USING PP2AB56ALPHASELECTIVE SMALL MOLECULE MODULATORS OF PROTEINPHOSPHATASE 2A AS A THERAPEUTIC STRATEGY FOR TREATING MYCDRIVENCANCERS
title_short TARGETED DEGRADATION OF THE MYC ONCOGENE USING PP2AB56ALPHASELECTIVE SMALL MOLECULE MODULATORS OF PROTEINPHOSPHATASE 2A AS A THERAPEUTIC STRATEGY FOR TREATING MYCDRIVENCANCERS
title_full TARGETED DEGRADATION OF THE MYC ONCOGENE USING PP2AB56ALPHASELECTIVE SMALL MOLECULE MODULATORS OF PROTEINPHOSPHATASE 2A AS A THERAPEUTIC STRATEGY FOR TREATING MYCDRIVENCANCERS
title_fullStr TARGETED DEGRADATION OF THE MYC ONCOGENE USING PP2AB56ALPHASELECTIVE SMALL MOLECULE MODULATORS OF PROTEINPHOSPHATASE 2A AS A THERAPEUTIC STRATEGY FOR TREATING MYCDRIVENCANCERS
title_full_unstemmed TARGETED DEGRADATION OF THE MYC ONCOGENE USING PP2AB56ALPHASELECTIVE SMALL MOLECULE MODULATORS OF PROTEINPHOSPHATASE 2A AS A THERAPEUTIC STRATEGY FOR TREATING MYCDRIVENCANCERS
title_sort targeted degradation of the myc oncogene using pp2ab56alphaselective small molecule modulators of proteinphosphatase 2a as a therapeutic strategy for treating mycdrivencancers
publisher Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate 2020
url http://rave.ohiolink.edu/etdc/view?acc_num=case1579905487094187
work_keys_str_mv AT farringtoncarolinecain targeteddegradationofthemyconcogeneusingpp2ab56alphaselectivesmallmoleculemodulatorsofproteinphosphatase2aasatherapeuticstrategyfortreatingmycdrivencancers
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