EntreMed Announces Publication Of Preclinical Results For ENMD-2076 In Triple-negative Breast Cancer
Predictive biomarkers of sensitivity to ENMD-2076 published in Clinical Cancer Research
ROCKVILLE, Md., Nov. 26, 2012 /PRNewswire/ -- EntreMed, Inc. (Nasdaq: ENMD), a clinical-stage pharmaceutical company developing targeted therapeutics for the treatment of cancer, 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.
Dr. Jennifer R. Diamond of the University of Colorado School of Medicine, who led the study, commented, "Triple-negative breast cancer is an aggressive breast cancer subtype which carries a high risk of developing metastasis. A major barrier to the successful treatment of metastatic TNBC is the lack of effective targeted anti-cancer agents. 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., EntreMed's Chief Executive Officer further commented, "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."
EntreMed, Inc. is a clinical-stage pharmaceutical company employing a drug development strategy primarily in the United States and China to develop targeted therapeutics for the global market. Its lead compound, ENMD-2076, a selective angiogenic kinase inhibitor, has completed several Phase 1 studies in solid tumors, multiple myeloma, and leukemia, and is currently completing a multi-center Phase 2 study in ovarian cancer. EntreMed, Inc. recently initiated a Phase 2 study of ENMD-2076 in triple-negative breast cancer.
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.
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Posted: November 2012