Addressing complexity of Notch in cancer: When less is more

DOMINGUEZ M; VILLEGAS SN; MIGH E; DA ROS VG; VALLEJO D; GARCIA CASTILLO J; GUTIERREZ PEREZ I; XARGAY S; COLOMER D; TORIBIO M; MIHÁLY J

Chicago

Conferencia; 56th Annual Drosophila Research Conference.; 2015

The Genetics Society of America

Despite recent therapeutic advances, cancer still remains a pressing health concern. Cancer is a cellular phenomenon that occurs within the context of normal tissues and a normal microenvironment within the organism. As such, one of the major challenges is to understand how the initiating oncogenic lesions that confer malignant properties on cells are integrated with, and perturb, the physiological processes that regulate cell proliferation and growth, invasion, migration, and metabolism. Our work over these years has contributed to show how inappropriate Notch signalling instructs abnormal growth through partnership with other signalling pathways and factors. Attempts to target tumours generated by cooperation have repeatedly failed to stop cancer due to secondary oncogene addiction, as it has been shown for Notch- Pten/Akt cooperative tumours. Moreover, Notch signalling has key roles in maintenance of barrier function at epithelial organs like the gastrointestinal track and in the differentiation of functionally critical cell types. As such, indiscriminate abrogation of Notch poses a drug discovery challenge. In this talk, I will discuss data from complementary large-scale cancer-causing genes and a recent proteomic analysis complemented with a high-throughput compound screen applied to Notch-Pten tumours. These studies identify unforeseen targets of the cross-talk between these important ´oncogenic´ pathways. Importantly, one of the compounds identified in flies was highly selective to kill human cancer cells carrying Notch activating mutations without affecting normal healthy cells, and with a relative low IC50. I will discuss opportunities and proposed strategies to target Notch signalling system in cancer.