Molecular pathogenesis and therapeutic targets in epithelial ovarian cancer

Abstract

Ovarian cancer, the most aggressive gynecologic cancer, is the foremost cause of death from gynecologic malignancies in the developed world. Two primary reasons explain its aggressive behavior: most patients present with advanced disease at diagnosis, and die of recurrences from disease that has become resistant to conventional chemotherapies. In this paper on epithelial ovarian cancer (EOC), we will review molecular alterations associated with the few precursor lesions identified to date, followed by the more commonly recognized processes of de novo carcinogenesis, metastasis, and the development of chemoresistance. We will propose a unifying model of ovarian epithelial tumorigenesis that takes into account various hypotheses. We will also review novel approaches to overcome the major problem of chemoresistance in ovarian cancer. Finally, we will discuss advances and new challenges in the development of mouse model systems to investigate EOC precursor lesions, progression, metastasis, and chemoresistance.

Epigenetic silencing of SFRP5 is related to malignant phenotype and chemoresistance of ovarian cancer through Wnt signaling pathway

“…The past few years have seen an enormous growth in our understanding of the mechanisms that regulate drug-induced apoptosis, arrest the cell cycle, and inhibit angiogenesis, and thus influence chemosensitivity. 41 One possible target to enhance chemosensitivity is to prevent drug efflux in cancer cells by blocking ATP-binding cassette transporters, 42 but a Phase III clinical trial showed no improvement in survival. Inhibitors of glutathione, 43 angiogenic molecules 44 and growth factor receptors 45 are the new therapeutic targets for treating ovarian cancer, but the outcomes are controversial and need further studies.…”

Extended weekly dose-dense paclitaxel/carboplatin is feasible and active in heavily pre-treated platinum-resistant recurrent ovarian cancer

“…This finding is of importance as platinum resistance ultimately becomes the dominant problem for most patients with ovarian cancer. The approach described here holds promise in that it may be coupled to molecularly targeted therapies that can either reverse acquired platinum resistance or enhance intrinsic platinum sensitivity (Gordon et al, 2005;Schilder et al, 2005;Alvero et al, 2006;Appleton et al, 2007;Cannistra et al, 2007;Chien et al, 2007). This approach may feasibly enhance efficacy to the point that survival gains may become worthwhile.…”

Mutations in the KRAS gene in ovarian tumors.

“…Advanced-stage disease display aggressive chemoresistant behavior with patients demonstrating a shorter median survival rate [11,12].…”