Targeting the EBFR and PI3K pathways as a therapeutic strategy for prostate cancer
Date
2015-04
Authors
Maleka, Sechaba
Journal Title
Journal ISSN
Volume Title
Publisher
Stellenbosch : Stellenbosch University
Abstract
ENGLISH ABSTRACT: Targeted therapy for prostate cancer may offer potential improvement over current
conventional therapies because of its specificity. Although conventional treatments
are effective, they are not curative and have several limitations. In prostate cancer,
activation of both the epidermal growth factor receptor (EGFR) and the
phosphatidylinositol 3 – kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)
pathway have been implicated in tumorigenesis and resistance to both conventional
and targeted anticancer therapies. Having a better understanding of the molecular
mechanisms involved in PCa development, progression and resistance to therapy,
could assist in the design of novel therapeutic strategies.
The objective of this study was to inhibit key molecular targets of the human
epidermal growth factor receptor signalling pathway and expose prostate cell lines to
doses of radiation, so as to establish potential therapeutic targets that may be
amenable to combined modality therapy, and formulate a cocktail of inhibitors to
evaluate its radiosensitising capability.
The EGFR/PI3K/mTOR pathway plays an important role in the radiosensitivity of the
human prostate carcinoma cell line (DU145) and the normal cell line (1542N). In our
study we have shown that AG-1478, an EGFR inhibitor, and BEZ-235, a dual
inhibitor of the PI3K/mTOR pathway, singly or in combination, at low and relatively
high radiation doses, resulted in radiosensitisation of DU145 cells. Radio-protection
was achieved in 1542N cells. AG-1478 had no effect on radiosensitivity.
AFRIKAANSE OPSOMMING: Geteikende terapies wens hul spesifisiteit teenoor konvensionele terapies vir prostaat kanker, mag potensieel verbetering offer. Konvensionele behandeling is wel effektief maar nie genesend nie wens ‘n aantal beperkings, sowel as die toksisiteit vir normale selle. In prostaat kanker is die aktivering van beide die epidermiese groei faktor reseptor (EGFR) en fosfatidielinositol 3-kinase/Akt/soogdier teiken vir rapamisien (mTOR) seingewing baan sterk betrek by tumor groeisel en weerstand teen konvensionele en geteikende anti-kanker terapies. Beter begrip van die molekulêre meganismes betrokke by prostaat kanker ontwikkeling, bevordering en weerstand teen terapie, kan die ontwerp van nuwe terapeutiese strategies ondersteun. Die doelwit van hierdie studie was om sleutel molekulêre teikens van die epidermiese groei faktor reseptor seingewing baan te inhibeer en om prostaat selle bloot te stel aan dosisse bestraling, om potensiële terapeutiese teikens te vestig wat vatbaar is vir gekombineerde modaliteit terapie, om ‘n mengsel van stremmiddels te formuleer, en om die straling gevoeligmaking bekwaamheid daarvan te evalueer. Die EGFR/PI3K/mTOR seingewingbaan speel ‘n belangrike rol in the radiosensitiwiteit van die menslike prostaat kanker sellyn (DU145) en die normale prostaat sellyn (1542N). Die studie bevind dat AG-1478, ‘n EGFR stremmer, en BEZ-235, ‘n tweevoudige beperker van die fosforinositied 3-kinase (PI3K) en soogdier teiken vir rapamisien (mTOR) seingewingbaan, enkel of in kombinasie die DU145 selle radiosensitiseer vir straling dosisse van 2 en 6 Gy. Stralings beskerming was verkry met die 1542N sellyn. AG-1478 het geen effek getoon op radiosensitiwiteit nie.
AFRIKAANSE OPSOMMING: Geteikende terapies wens hul spesifisiteit teenoor konvensionele terapies vir prostaat kanker, mag potensieel verbetering offer. Konvensionele behandeling is wel effektief maar nie genesend nie wens ‘n aantal beperkings, sowel as die toksisiteit vir normale selle. In prostaat kanker is die aktivering van beide die epidermiese groei faktor reseptor (EGFR) en fosfatidielinositol 3-kinase/Akt/soogdier teiken vir rapamisien (mTOR) seingewing baan sterk betrek by tumor groeisel en weerstand teen konvensionele en geteikende anti-kanker terapies. Beter begrip van die molekulêre meganismes betrokke by prostaat kanker ontwikkeling, bevordering en weerstand teen terapie, kan die ontwerp van nuwe terapeutiese strategies ondersteun. Die doelwit van hierdie studie was om sleutel molekulêre teikens van die epidermiese groei faktor reseptor seingewing baan te inhibeer en om prostaat selle bloot te stel aan dosisse bestraling, om potensiële terapeutiese teikens te vestig wat vatbaar is vir gekombineerde modaliteit terapie, om ‘n mengsel van stremmiddels te formuleer, en om die straling gevoeligmaking bekwaamheid daarvan te evalueer. Die EGFR/PI3K/mTOR seingewingbaan speel ‘n belangrike rol in the radiosensitiwiteit van die menslike prostaat kanker sellyn (DU145) en die normale prostaat sellyn (1542N). Die studie bevind dat AG-1478, ‘n EGFR stremmer, en BEZ-235, ‘n tweevoudige beperker van die fosforinositied 3-kinase (PI3K) en soogdier teiken vir rapamisien (mTOR) seingewingbaan, enkel of in kombinasie die DU145 selle radiosensitiseer vir straling dosisse van 2 en 6 Gy. Stralings beskerming was verkry met die 1542N sellyn. AG-1478 het geen effek getoon op radiosensitiwiteit nie.
Description
Thesis (MSc)--Stellenbosch University, 2015.
Keywords
PI3K Pathway, Prostate Cancer, Radiosensitivity, EGFR, UCTD