6 research outputs found
Cyclooxygenase-2 blockade can improve efficacy of VEGF-targeting drugs
Anti-angiogenic therapies were approved for different cancers. However,
significant primary and secondary resistance hampers efficacy in several tumor types
including breast cancer. Thus, we need to develop clinically applicable strategies to
enhance efficacy of anti-angiogenic drugs.
We report that anti-angiogenic therapies can induce upregulation of
cyclooxygenase-2 (Cox-2) and of its product prostaglandin E2 (PGE2) in breast cancer
models. Upon Cox-2 inhibition PGE2 levels were normalized and efficacy of antivascular endothelial growth factor receptor 2 (anti-VEGFR-2) antibodies and sunitinib
was enhanced. Interestingly, both treatments exerted additive anti-angiogenic
effects. Following Cox-2 inhibition, we observed reduced infiltration of tumors with
cancer-associated fibroblasts (CAFs) and lower levels of pro-angiogenic factors active
besides the VEGF axis including hepatocyte growth factor (HGF) and basic fibroblast
growth factor (FGF2). Mechanistic studies indicated that Cox-2 inhibition reduced
PGE2-induced migration and proliferation of CAFs via inhibiting phosphorylation of Akt.
Hence, Cox-2 inhibition can increase efficacy of anti-angiogenic treatments and
our findings might pave the road for clinical investigations of concomitant blockade
of Cox-2 and VEGF-signaling
Determination of the Cancer Genome Atlas (TCGA) Endometrial Cancer Molecular Subtypes Using the Variant Interpretation and Clinical Decision Support Software MH Guide
Background: The Cancer Genome Atlas (TCGA) network (United States National Cancer Institute) identified four molecular endometrial cancer (EC) subtypes using an extensive multi-method approach. The aim of this study was to determine the four TCGA EC molecular subtypes using a single-method whole-exome sequencing (WES)-based approach provided by MH Guide (Molecular Health, Heidelberg, Germany). Methods: WES and clinical data of n = 232 EC patients were obtained from TCGA. The four TCGA EC molecular subtypes designated as (i) Mutated Polymerase ε (POLE), (ii) Microsatellite Instability (MSI), (iii) Copy Number (CN) low and, (iv) CN-high were determined using the MH Guide software. The prognostic value of the subtypes determined by MH Guide were compared with the TCGA classification. Results: Analysis of WES data using the MH Guide software led to the precise identification of the four EC molecular subtypes analogous to the TCGA classification. Both approaches displayed high concordance in terms of prognostic significance. Conclusions: The multi-method-based TCGA EC molecular subtypes can reliably be reproduced by the single-method-based MH Guide approach. The easy-to-implement single-method MH Guide approach represents a promising diagnostic tool