Molecular alterations for targeting therapy in metastatic gynecologic cancer

Endometrial cancer is the most common and ovarian cancer the most lethal pelvic gynaecologic malignancies. Improved treatment for metastatic disease and reliable predictors for response to therapeutics are needed. Serous papillary endometrial- and ovarian carcinomas share an aggressive course of the disease. This project is an integrated part of a national and international prospective multicenter study of tissue from primary and metastatic lesions aiming to facilitate implementation of molecularly based targeted therapy. We have recently identified new potential targets for treatment of aggressive gynecologic cancer such as FGFR2 and the PI3Kinas signaling pathway (PNAS 2008 and PNAS 2009). In this project we plan to take our previous studies of global m olecular classification of primary tumours to a new level with global characterisation of genetic alterations in a unique sample set of fresh tissues from corresponding primary- and metastatic lesions. The main hypothesis is that the molecular profile of metastatic lesion is of particular relevant for disease spread and targeting such by therapy. The findings from the comprehensive profiling of lesions by mRNA array, SNP array and deep sequencing will be related to phenotype, findings by functional imagin g and response to therapy. Genetic alterations in primary tumors and metastatic lesions will be related to alterations in expression levels for specific signalling pathways potentially targetable by new drugs. A larger validation set of primary and metast atic lesions from formalin fixed paraffin embedded (FFPE) tissues will be used for validation of amplifications of candidate genes by Fluorescence in Situ Hybridization (FISH). The ultimate goal is to apply the new knowledge regarding distribution of gene tic alterations in metastatic lesions to improve the design of trials with molecularly targeted therapy.