Combination therapeutic strategy for the treatment of serous ovarian epithelial cancers and ovarian granulosa cell tumours
Combination therapeutic strategy for the treatment of serous ovarian epithelial cancers and ovarian granulosa cell tumours is a Research Project for the Steroid Receptor Biology Research Group, under the Centre for Endocrinology and Metabolism.
Overcoming chemoresistance remains a key problem in the treatment of advanced ovarian cancer and consequently, new substances to enhance and support the activity of cytotoxic drugs are urgently needed. Therapeutic targets under investigation for ovarian cancer are the nuclear hormone receptors.
We identified that a nuclear receptor, peroxisome proliferator activation receptor gamma (PPARγ) is highly expressed in serous epithelial ovarian cancer (EOC) and in granulosa cell tumours (GCT), thus presenting a potential therapeutic target for this disease. The potential of PPARγ agonists as anticancer agents has attracted considerable interest, including the treatment of other endocrine malignancies. Additionally, a key anti-apoptotic protein, X-linked inhibitor of apoptosis (XIAP), is also highly expressed in EOC and GCT and is central in protecting cancer cells from apoptosis. As XIAP inhibits the apoptotic pathways, it is an attractive target for the development of novel therapeutic strategies for the treatment of malignancy. Small molecule inhibitors targeting XIAP are in various stages of development, from preclinical to phase II clinical trials. Antagonism of XIAP in vitro and in vivo has been shown to lower the apoptotic threshold and thereby sensitise tumour cells to the effects of chemotherapy, enabling the use of lower doses with the potential for fewer toxicities. Our findings establish a potential novel therapeutic strategy for EOC and GCT, combining inhibition of XIAP activity with activation of PPARγ.
This project aims to demonstrate, using a xenograft model, the efficacy of XIAP inhibition in combination with PPARγ-regulated genes in GCT- and EOC-derived cells, and their contribution to initiating apoptosis and/or differentiation.
Associate Professor Tom Jobling, Gynaecology Oncology, Monash Health
Dr Andrew Stephens, MIMR-PHI Institute, OCRF Research Fellow
Dr Adam Rainczuk, MIMR-PHI Institute, OCRF Witchery Research Fellow
Associate Professor John Silke, Walter & Eliza Hall Institute
Mr Powel Crosley, Granulosa Cell Tumor Research Foundation
Chu, S., Alexiadis, M. and Fuller, P.J.Proteasome Inhibition by bortezomib decreases proliferation and increases apoptosis in ovarian granulosa cell tumors. Reproductive Sciences 16:397-407, 2009.
Chu, S. Nishi, Y., Yanase, T., Nawata, H. and Fuller, P.J.Transrepression of estrogen receptor β signaling by nuclear factor-kB in ovarian granulosa cells. Molecular Endocrinology 18: 1919-1928, 2004.
Chu, S., Alexiadis, M. and Fuller, P.J.Expression, mutational analysis and in vitro response of imatinib mesylate and nilotinib target genes in ovarian granulosa cell tumors. Gynecologic Oncology 108: 182–190, 2008.
Alexiadis, A., Eriksson, N., Jamieson, S., Davis, M., Drummond, A.E., Chu, S., Clyne, C.D, Muscat, G.E, and Fuller, P.J.Nuclear receptor profiling of ovarian granulosa cell tumors. Hormones and Cancer 2:157-69, 2011.
Jamieson, S. and Fuller, P.J.Characterization of the inhibitor of kappaB kinase (IKK) complex in granulosa cell tumors of the ovary and granulosa cell tumor-derived cell lines. Hormones and Cancer 4: 277-292, 2013.