Age-related mTOR in ovarian and endometrial cancers

Ovarian and endometrial cancers are the most prevalent gynaecologic cancers in aged women and account for significant mortality worldwide. The incidence of both these cancers increases with advancing age. mTOR signalling is a major regulator of aging as suppression of this pathway extends lifespan in model organisms. Overactive mTOR signalling is present in up to 80% of ovarian cancer (OvCa) samples and is associated with poor prognosis. In addition, genetic alterations in this pathway via mutations and/or amplifications are often encountered in endometrial cancers. However, the exact mechanism through which mTOR signalling contributes to the functional and morphological changes in the ovary and uterus of aged women is not fully understood. The aims of this thesis were to unravel the complex interplay between mTOR and aging in pathogenesis of female reproductive tract cancers. Importantly, we sought to determine how age-related increase in mTOR activity contributes to the development of pathological lesions in ovary and uterus and whether this could be ameliorated by the utilization of mTOR inhibitors or by genetic interventions. We also aimed to determine the mechanisms of acquired resistance to mTOR therapy in endometrial cancer. Our results demonstrated that abnormal, hyperplastic and invasive growths occur in the ovarian surface epithelium (OSE) and endometrium of aged mice and women, which represent precancerous lesions. To understand whether hyperactive mTOR signalling is responsible for the development of these pathological changes, we utilized three well established mouse models, Pten heterozygous (Pten^+/-), Pten overexpressing (Pten^tg) and rapamycin treated mice. Genetic deletion or overexpression of Pten (a negative regulator of mTOR signalling) significantly altered the age-associated changes in ovaries and uteri of mice. Furthermore, pharmacological inhibition using rapamycin or rapalogs significantly reduced both OSE and endometrial hyperplasia. We also validated the efficacy of two FDA- approved mTOR drugs (Everolimus and BEZ235) in controlling growth of human ovarian and endometrial cancer cells. Finally, to characterize the mechanisms of resistance to mTOR inhibitors, we developed an in vitro model of Everolimus- resistant endometrial cancer cell line. We have shown that upregulated Src kinase is a mediator of resistance to mTOR therapy, which can be reverted using a combination of mTOR and Src pathway inhibitors. Collectively, we have established the role of mTOR signalling in age-related OSE and endometrial pathologies. Therefore, therapeutic targeting of mTOR alone or in combination with other pathway inhibitors might be a viable strategy for treating age-related gynaecological cancers.