Monday, November 26, 2012

Study Hints of New Therapy for TNBC with p53 Mutation

A preclinical study shows oral Aurora A/angiogenic kinase inhibitor, ENMD-2076 can be effective against triple-negative breast cancer.  Published in Clinical Cancer Research, the research  also identified predictive biomarkers that may be useful in selecting patients that are particularly sensitive to ENMD-2076. Tumors with the p53 mutation and increased p53 expression were especially sensitive to this treatment. 
The study analyzed twenty-nine breast cancer cell lines representative of the wide variety of clinically defined breast cancer subtypes that were exposed to ENMD-2076.  Results indicated that  ENMD-2076 was effective against the cell lines of the TNBC subtype  and much less effective against luminal and HER2-amplified subtypes.  Within TNBC tumors, cell lines with a p53 mutation and increased p53 expression were more sensitive to the the effects of ENMD-2076 exposure than those with decreased p53 expression.  This means that future clinical trials with ENMD-2076 may focus specifically on TNBC tumors with the p53 mutation.
According to Jennifer R. Diamond MD of the University of Colorado School of Medicine, who led the research, "Through this study, we show that ENMD-2076 has activity against preclinical models of breast cancer with more robust activity against TNBC.  The study also supports further clinical investigation of ENMD-2076 in patients with metastatic TNBC with an emphasis on the continued development of p53-based predictive biomarkers."
Ken Ren, Ph.D.,  Chief Executive Officer of EntreMed, which produces ENMD-2076, said, "One of the major challenges for the development of a target therapy for cancer is the identification of a responsive subtype with a predictive biomarker. In our previous Phase 1 study, we observed a patient with TNBC who had failed multiple chemotherapy regimens then had clinically significant stabilization of disease for 41 weeks after ENMD-2076 treatment.  The benchmark of median duration after first line therapy in such patients with metastasis is just 12 weeks. This pre-clinical study illustrated scientific insight into the selective sensitivity of TNBC to ENMD-2076 with direct correlation to p53 mutation and over expression. It provides strong support for the rational of our ongoing Phase 2 TNBC trial. Upon further confirmation clinically, it may also provide guidance on future trials for patient selection, and may increase the probability of success. We are continuing to enroll patients in the ongoing Phase 2 trial and anticipate the initiation of a second site for this trial soon. We remain on track with our clinical development activities and expect our progress to accelerate in the coming months and year."
From EntreMed: ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers. ENMD-2076 has shown promising activity in Phase 1 clinical trials in solid tumor cancers, leukemia, and multiple myeloma. ENMD-2076 is currently completing a Phase 2 trial for ovarian cancer.  EntreMed, Inc. recently initiated a Phase 2 study of ENMD-2076 in triple-negative breast cancer.
SOURCE: " "Predictive Biomarkers of Sensitivity to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Breast Cancer Models," Clinical Cancer Research, November 7, 2012.
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