Notch signaling pathway in breast cancer stem cells: A promising therapeutic target

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ANN ARBOR, Mich. – A new collaborative study from the GRU Cancer Center at Georgia Regents University and the University of Michigan Comprehensive Cancer Center provides direct evidence for the role of the Notch pathway in breast cancer stem cell activity as demonstrated by a Notch reporter system. Notch signaling regulates embryonic and tissue-specific stem cells, which are altered in a number of human malignancies, including breast cancer.

The investigators, led by Hasan Korkaya, Ph.D., at the GRU Cancer Center, found that breast cancer cells with elevated Notch activity displayed cancer stem cell properties and also had the ability to initiate tumors in serial transplantation assays in mouse xenografts. Upon analyzing a large number of breast cancer samples, the team’s findings suggest that the expression of the Notch4 isoform is significantly correlated with elevated Notch activity and poor patient survival.

The study has been published in the American Association for Cancer Research journal, Molecular Cancer Therapeutics.

“Notch is a critical developmental pathway playing important physiological roles, and thus alteration of this pathway leads to dramatic pathological conditions including cancer. Fortunately, we now have the inhibitors to target this pathway to circumvent its unwanted activities,” Korkaya says.

Due to the clinical relevance of the Notch signaling pathway, a number of Notch-targeting inhibitors and neutralizing antibodies are in preclinical and early clinical development.  One such drug is MRK-003, the gamma-secretase inhibitor used in these studies, which was provided by Merck & Co., Inc.

“We were the first to identify breast cancer stem cells more than a decade ago. I am now pleased to see that the molecular characterization of these breast cancer stem cells is leading the way for alternative therapeutics. As a matter of fact, this study complements and provides molecular explanation for our previous clinical phase I study where we showed the benefit of a gamma-secretase or Notch inhibitor in patients,” says study author Max Wicha, M.D., director emeritus of the University of Michigan Comprehensive Cancer Center, emphasizing the clinical relevance of such breast cancer stem cell-specific pathways.

The study’s authors recognize that additional pre-clinical and early clinical testing is necessary to establish the use of Notch inhibitors in breast cancer patients. Furthermore, they also believe that the Notch pathway may be critical player in cancer stem cells from other types of malignancies.

Reference: D’Angelo RC, Ouzounova M, Davis A, Choi D, Tchuenkam SM, Kim G, Luther T, Quraishi AA, Senbabaoglu Y, Conley SJ, Clouthier SG, Hassan KA, Wicha MS, Korkaya H. Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity. Mol Cancer Ther.  2015, 10.1158/1535-7163. MCT-14-00228

Disclosure: Wicha has financial holdings and is a scientific adviser for OncoMed Pharmaceuticals; is a scientific adviser for Verastem, Paganini and MedImmune; and receives research support from Dompe Pharmaceuticals and MedImmune.  The Notch inhibitor MRK-003 was provided by Merck & Co., Inc.