2012 © Institute for Molecular Medicine Finland FIMM
Academy Professor Kari Alitalo
Primary Affiliation:
Faculty of Medicine, University of Helsinki
Title of the FIMM-Specific Research Project:
Targeting Prox1 in colorectal cancer progression
Abstract:
We have discovered that the homeobox transcription factor PROX1 is overexpressed in approximately 70% of human colorectal carcinomas (CRCs) as well as in mouse models of intestinal cancer with abnormal ß-catenin/TCF signaling. Importantly, PROX1 expression marks the transition from benign colon adenoma to carcinoma in situ, and its loss inhibits growth of human colorectal tumor xenografts and intestinal adenomas in Apc(min/+) mice, while its transgenic overexpression promotes colorectal tumorigenesis. Furthermore, in intestinal tumors PROX1 is a direct and dose-dependent target of the beta-catenin/TCF signaling pathway, responsible for the neoplastic transformation. Furthermore, our results demonstrate not only that PROX1 is important for the malignant progression of CRC tumors, but also show the tissue-specific regulation and function of PROX1, and warrant further studies of PROX1 as a potential target of drug development. - We want to develop compounds and dominant negative constructs that inhibit PROX1 activity in CRC and to validate their effect in cultured cells and ultimately in mouse tumor models. We aim to use synthetic lethality high-throughput assays for the identification of compounds that inhibit PROX1 activity or kill PROX1+ cells in CRC and to test them in vivo.
Contact Information:
Kari Alitalo
M.D., Ph.D., Academy Professor
Molecular Cancer Biology Program
Biomedicum Helsinki
Haartman Institute
PO Box 63 (Haartmaninkatu 8)
FI-00014 University of Helsinki
Finland
Tel. +358 9 191 25511
Fax. +358 9 191 25510
kari.alitalo@helsinki.fi