Inhibiting Myc in cancer using Omomyc. From defining the fundamental mechanism of action to its pharmacological application

dc.contributor
Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular
dc.contributor.author
Jauset González, Toni
dc.date.accessioned
2018-09-27T06:20:06Z
dc.date.available
2020-06-21T02:00:14Z
dc.date.issued
2018-06-22
dc.identifier.isbn
9788449079856
en_US
dc.identifier.uri
http://hdl.handle.net/10803/662770
dc.description.abstract
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.
en_US
dc.format.extent
149 p.
en_US
dc.format.mimetype
application/pdf
dc.language.iso
eng
en_US
dc.publisher
Universitat Autònoma de Barcelona
dc.rights.license
L'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.uri
http://creativecommons.org/licenses/by-nc-nd/4.0/
*
dc.source
TDX (Tesis Doctorals en Xarxa)
dc.subject
Myc
en_US
dc.subject
Omomyc
en_US
dc.subject
Càncer
en_US
dc.subject
Cáncer
en_US
dc.subject
Cancer
en_US
dc.subject.other
Ciències Experimentals
en_US
dc.title
Inhibiting Myc in cancer using Omomyc. From defining the fundamental mechanism of action to its pharmacological application
en_US
dc.type
info:eu-repo/semantics/doctoralThesis
dc.type
info:eu-repo/semantics/publishedVersion
dc.subject.udc
577
en_US
dc.contributor.authoremail
tjauset@vhio.net
en_US
dc.contributor.director
Soucek, Laura
dc.contributor.tutor
Lizcano de Vega, José Miguel
dc.embargo.terms
24 mesos
en_US
dc.rights.accessLevel
info:eu-repo/semantics/openAccess


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