EntreMed ENMD announced today the publication of favorable results of a
preclinical study in breast cancer of its oral Aurora A/angiogenic kinase
inhibitor, ENMD-2076.
The article, entitled "Predictive Biomarkers of Sensitivity to the Aurora and
Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Breast Cancer Models"
reports evidence that ENMD-2076 exhibited robust anticancer activity against
breast cancer cell lines lacking expression of the estrogen receptor (ER),
progesterone receptor (PR) and without HER2‑amplification: a particularly
difficult to treat subtype termed "triple-negative" breast cancer (TNBC).
TNBC is associated with a shortened disease-free and overall survival at all
stages of diagnosis when compared to other breast cancer subtypes. Candidate
predictive biomarkers were also identified which may be useful in selecting
patients that are particularly sensitive to this compound, ENMD-2076, in the
future.
In this study, a diverse panel of twenty-nine breast cancer cell lines
representative of the clinically defined breast cancer subtypes were exposed
to ENMD-2076 and the effects on proliferation, apoptosis, and cell cycle
distribution were evaluated. ENMD-2076 demonstrated more robust activity
against cell lines of the TNBC subtype compared to the luminal and
HER2-amplified subtypes. This in vitro activity was confirmed in vivo, in
MDA-MB-468 and MDA-MB-231 TNBC xenografts. Baseline gene expression profiling
and pathway analysis of the panel revealed that p53 and G1/S cell cycle
pathways were upregulated in the more sensitive cell lines. Within the TNBC
subset itself, cell lines with a p53 mutation and increased p53 expression
were more sensitive to the cytotoxic and pro-apoptotic effects of ENMD-2076
exposure than cell lines with decreased p53 expression. This information
provides the basis for a predictive biomarker strategy to explore in future
clinical trials with ENMD-2076.
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