De grootste kennisbank van het HBO

Inspiratie op jouw vakgebied

Vrij toegankelijk

Terug naar zoekresultatenDeel deze publicatie

Combined targeted therapy and its influence on tumor immune infiltrates in a mouse model of human melanoma

Rechten: Alle rechten voorbehouden

Combined targeted therapy and its influence on tumor immune infiltrates in a mouse model of human melanoma

Rechten: Alle rechten voorbehouden

Samenvatting

The mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways have been identified as the most common pathways that mediate oncogenic transformation in melanoma. An expanding range of small molecule inhibitors have been developed to target these pathways, and some have been shown to induce survival benefits for melanoma patients.
Melanoma is also thought to be highly immunogenic and in addition to small molecule inhibitors, immunotherapeutic approaches are being studied to increase progression free survival and survival. The aim of this study is to analyse potential synergy of small molecule therapies targeting both the MAPK and the PI3K pathway and define combinations of targeted therapies that possibly can be combined with immunotherapeutic approaches based on immune cell populations alterations in the tumor.

To determine the effects of the different MAPK and PI3K pathway inhibitors on the relative expression of the downstream molecules of these pathways in vitro, BRAF and NRAS mutated human melanoma cells were treated with single or combined combination of MAPK and PI3K pathway inhibitors. As expected, after treatment with combined MAPK and PI3K pathway inhibitors the relative expression of posphorylated ERK and phosphorylated S6 was downregulated, indicating both pathways can be simultaneously inhibited in vitro. To determine the effects of combined targeted therapies in vivo a Tyr::CreERT2;PtenLoxP/LoxP;BrafCA/+ inducible mouse model was used. Tumors from this mouse model are heterozygote for the BrafV600E mutation and are tumor suppressor gene phosphate-and-tensin-homologue (Pten) deficient. Tumor-bearing mice were treated with combined BRAF, MEK, mTORC1 and PI3K inhibitors. The effects of combined treatment on tumor outgrowth and tumor control were analyzed. Subsequently, immune cell populations in the tumor were characterized and the frequency was determined. Combined treatment MAPK and PI3K pathway inhibition resulted in a stronger average decreased tumor size over time compared to single MAPK pathway inhibition. In addition, frequencies of CD8+ T cells, NK cells and NK T cells have significantly increased of combined MAPK and PI3K pathway inhibition compared to mock treatment and furthermore, macrophages and myeloid cells were significantly decreased. The ratios of CD8+ and CD4+ T cells versus Tregs did show the most increase after BRAFi and MEKi treatment, whereas the ratios of CD8+ and CD4+ T cells versus MDSCs show the most increase after single BRAFi treatment. Combined MAPK and PI3K pathway however did show an increase compared to mock treatment, but not to the same extend as BRAFi/MEKi treatment or single BRAFi treatment.

Considering the most average decreased tumor sizes after treatment of 53 days and the increased immune cells populations present in the tumor after 7 days of treatment, we can conclude that the MAPK and PI3K pathway inhibition is synergistic in vivo and also a promising targeted therapy to combine with immunotherapeutic approaches. Based on tumor decrease and the ratios of immune cell populations present in the tumor microenvironment, BRAFi and MEKi treatment is also a promising suggested therapy to combine with immunotherapy as treatment for metastatic melanoma patients.

Toon meer
OrganisatieAvans Hogeschool
OpleidingBiologie en Medisch Laboratoriumonderzoek-Breda
AfdelingATGM Academie voor de technologie van Gezondheid en Milieu
PartnerNederlands Kanker Instituut, Antoni van Leeuwenhoek
Datum2014-06-04
TypeBachelor
TaalEngels

Op de HBO Kennisbank vind je publicaties van 26 hogescholen

De grootste kennisbank van het HBO

Inspiratie op jouw vakgebied

Vrij toegankelijk