A Novel Combination Treatment for Ovarian Granulosa Cell Tumors
Abstract
Ovarian granulosa cell tumors (GCT) arise due to dysfunction of granulosa cells within the ovary. They represent a unique subset of malignant ovarian tumors, accounting for approximately five to eight percent of all ovarian cancer. Unfortunately, due to their less common prevalence, these cancers are often not incorporated in ovarian cancer research, which is primarily focused on the more common ovarian epithelial cancers. Our research centre represents one of the few international research programs dedicated to GCT research. GCT have an unexplained propensity for late recurrence and approximately eighty percent of patients with advanced or recurrent tumors die from their disease. Although GCT are generally thought to have a better prognosis than epithelial tumors due to hormonal symptoms making an early diagnosis possible. But despite this, once surgery is no longer an option, current therapies have very poor success rates, presenting the very clear need for development of novel and targeted therapies. Despite the devastating impact of this disease on affected women, remarkably little is known of the molecular changes that give rise to GCT, other than >97% of adult GCT contain a specific common mutation [in] an early developmental gene known as FOXL2. However, whilst this gene is important for the genesis of this disease, it cannot be used as a direct target for treatment due to its being highly related to other genes vital for normal function. Accordingly, our studies have centred on investigating cellular pathways that play a critical role in the pathogenesis of GCT. These studies have led to discovering a key survival pathway and a nuclear hormone receptor that has presented as a promising targeted treatment. Our preliminary work has discovered that a nuclear hormone receptor (PPARgamma) and a key survival protein (XIAP) are overexpressed in this disease. PPARgamma has been implicated in several diseases including obesity, diabetes, and polycystic ovarian syndrome. Importantly, medicines that activate this receptor have been developed for the treatment of diabetes and have also been shown to have positive effects for the treatment of some cancers. Due to the importance of XIAP in protecting cells from dying, it too has become an attractive therapeutic target for novel anti-cancer treatment. There are now inhibitors to this protein that have demonstrated good anti-cancer activity in preclinical studies, and several have already passed primary phase clinical trials, suggesting that these compounds are well tolerated. Though XIAP inhibitors have shown some efficacy as single agents, the majority of studies have shown increased promise when used in a rational drug combination strategy. Leveraging preliminary work we have undertaken giving convincing results, this proposal will demonstrate the therapeutic potential of using a combination of medicines, targeting both of these proteins to achieve a more effective way of treatment. These studies will, in addition, have the potential to provide critical insights into the pathogenesis of this disease for development of novel targeted therapeutic options for the more aggressive and recurrent forms of GCT. GCT is non-discriminatory, affecting women in all areas of society. This proposal will result in findings that will support all patients including those in less well-served areas, be it on the basis of socio-economic status or geographical location. Knowledge generated from this study will also lead to well-validated best practice standard of care including referral to specialised centres where appropriate testing can be performed. The results from this research will be widely promulgated so that all women, including military Service members, their Families, and other military beneficiaries, and their doctors will have access to the appropriate information with respect to choice of therapy. This is inclusive of indigenous populations that are doubly disadvantaged in the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810263
Entities
People
- Simon Chu
Organizations
- Monash University
- United States Army