Inhibiting Myc in cancer using Omomyc

Identifying and targeting cancer cell components that play non-degenerate and non-redundant functions within cancers could lead to the development of more effective therapies. Myc is considered a prime example of such a target, and has been characterized as a downstream effector of multiple oncogeni...

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Autor: Jauset González, Toni
Tipo de recurso: tesis doctoral
Fecha de publicación:2018
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:201240
Acceso en línea:https://ddd.uab.cat/record/201240
Access Level:acceso abierto
Palabra clave:Cèl·lules canceroses
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spelling Inhibiting Myc in cancer using Omomycfrom defining the fundamental mechanism of action to its pharmacological applicationJauset González, ToniCèl·lules cancerosesIdentifying and targeting cancer cell components that play non-degenerate and non-redundant functions within cancers could lead to the development of more effective therapies. Myc is considered a prime example of such a target, and has been characterized as a downstream effector of multiple oncogenic pathways. Indeed, several studies have shown that inhibiting Myc displays notable therapeutic potential against different types of cancer. However, targeting Myc pharmacologically - directly or indirectly - is still considered challenging. Use of the Myc dominant negative mutant termed Omomyc provided the first evidence of the efficacy and safety of targeting Myc and displayed one of the most outstanding anti-tumorigenic potentials to date. This thesis project is divided into two major tasks: firstly, we aimed to better determine the source of Omomyc's therapeutic effect, which could provide clues on how to develop better Myc inhibitors; Secondly, despite the claims that Omomyc itself could not be used as a drug, we assessed different ways in which it could be effectively delivered to cancer cells to validate the first Omomyc-based drugs. In the context of our first task, by expressing Omomyc in a panel of lung cancer cells lines, we showed for the first time a gain-of-function of Omomyc, which intriguingly re-locates endogenous Max on Myc-unrelated DNA regions, thus potentially acting not only as a Myc inhibitor but also producing additional effects within cancer cells. Moreover, its dimerization with endogenous Max and the occupancy of DNA were identified as key effectors of Omomyc's anti-tumorigenic efficacy. In the context of generating the first Omomyc-based pharmacological approaches, Omomyc was first produced as a polypeptide. Remarkably, we determined that its systemic administration is safe and effective against subcutaneously implanted lung cancer cells, both as monotherapy and in combination with standard chemotherapy. Second, we generated Omomyc-encapsulating liposomes, which are able to improve the cellular uptake of the polypeptide and its nuclear localization. Finally, we provided the first evidence that Omomyc could be delivered as mRNA into cells that will translate it into a functional nuclear peptide product. 6 Together, our results provide insights into Omomyc's mechanism of action that might be used to develop new therapeutic approaches, including more effective Omomyc-derived drugs. Furthermore, we show that these could be delivered to cancer cells as cell-penetrating peptides (CPPs), liposomes and/or mRNA, providing an arsenal of tools to effectively and safely inhibit the Myc oncogene in the clinic.Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia MolecularSoucek, LauraLizcano de Vega, José Miguel 22018-01-0120182018-01-01Tesi doctoralhttp://purl.org/coar/resource_type/c_db06VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/doctoralThesisapplication/pdfhttps://ddd.uab.cat/record/201240reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2012402026-06-06T12:50:31Z
dc.title.none.fl_str_mv Inhibiting Myc in cancer using Omomyc
from defining the fundamental mechanism of action to its pharmacological application
title Inhibiting Myc in cancer using Omomyc
spellingShingle Inhibiting Myc in cancer using Omomyc
Jauset González, Toni
Cèl·lules canceroses
title_short Inhibiting Myc in cancer using Omomyc
title_full Inhibiting Myc in cancer using Omomyc
title_fullStr Inhibiting Myc in cancer using Omomyc
title_full_unstemmed Inhibiting Myc in cancer using Omomyc
title_sort Inhibiting Myc in cancer using Omomyc
dc.creator.none.fl_str_mv Jauset González, Toni
author Jauset González, Toni
author_facet Jauset González, Toni
author_role author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular
Soucek, Laura
Lizcano de Vega, José Miguel
dc.subject.none.fl_str_mv Cèl·lules canceroses
topic Cèl·lules canceroses
description Identifying and targeting cancer cell components that play non-degenerate and non-redundant functions within cancers could lead to the development of more effective therapies. Myc is considered a prime example of such a target, and has been characterized as a downstream effector of multiple oncogenic pathways. Indeed, several studies have shown that inhibiting Myc displays notable therapeutic potential against different types of cancer. However, targeting Myc pharmacologically - directly or indirectly - is still considered challenging. Use of the Myc dominant negative mutant termed Omomyc provided the first evidence of the efficacy and safety of targeting Myc and displayed one of the most outstanding anti-tumorigenic potentials to date. This thesis project is divided into two major tasks: firstly, we aimed to better determine the source of Omomyc's therapeutic effect, which could provide clues on how to develop better Myc inhibitors; Secondly, despite the claims that Omomyc itself could not be used as a drug, we assessed different ways in which it could be effectively delivered to cancer cells to validate the first Omomyc-based drugs. In the context of our first task, by expressing Omomyc in a panel of lung cancer cells lines, we showed for the first time a gain-of-function of Omomyc, which intriguingly re-locates endogenous Max on Myc-unrelated DNA regions, thus potentially acting not only as a Myc inhibitor but also producing additional effects within cancer cells. Moreover, its dimerization with endogenous Max and the occupancy of DNA were identified as key effectors of Omomyc's anti-tumorigenic efficacy. In the context of generating the first Omomyc-based pharmacological approaches, Omomyc was first produced as a polypeptide. Remarkably, we determined that its systemic administration is safe and effective against subcutaneously implanted lung cancer cells, both as monotherapy and in combination with standard chemotherapy. Second, we generated Omomyc-encapsulating liposomes, which are able to improve the cellular uptake of the polypeptide and its nuclear localization. Finally, we provided the first evidence that Omomyc could be delivered as mRNA into cells that will translate it into a functional nuclear peptide product. 6 Together, our results provide insights into Omomyc's mechanism of action that might be used to develop new therapeutic approaches, including more effective Omomyc-derived drugs. Furthermore, we show that these could be delivered to cancer cells as cell-penetrating peptides (CPPs), liposomes and/or mRNA, providing an arsenal of tools to effectively and safely inhibit the Myc oncogene in the clinic.
publishDate 2018
dc.date.none.fl_str_mv 2
2018-01-01
2018
2018-01-01
dc.type.none.fl_str_mv Tesi doctoral
http://purl.org/coar/resource_type/c_db06
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/201240
url https://ddd.uab.cat/record/201240
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
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