Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Targeting mTOR signaling in human ovarian cancer (#125)

Pradeep Tanwar 1
  1. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callghan, NSW, Australia

Ovarian cancer (OvCa) is one of the most common gynaecological cancers with
approximately 225,500 new cases diagnosed and 140,200 deaths yearly reported
worldwide. The incidence rates of OvCa are highest in the western world, where it is
the leading cause of death from gynaecological cancers. mTOR (mammalian Target
of Rapamycin) activation is frequently observed and associated with worst prognosis
for the human ovarian cancer patients. Different mTOR inhibitors are currently in
human ovarian cancer clinical trials. However, role of mTOR signaling in the
pathogenesis of ovarian cancer is unknown. We have shown frequent alterations in
major tumor suppressor genes (LKB1, TSC1, TSC2, and PTEN) involved in mTOR
signaling in human ovarian serous cancer (HOSC). LKB1 (Liver Kinase B1) gene
was deleted in up to 70% of patients. Loss of LKB1 protein and concurrent increase
in mTOR activity was observed in 52% of HOSC tissue samples and 70% of the
HOSC cell lines. Our conditional deletion of Lkb1 (Lkb1cko) in mouse ovarian surface
epithelial (OSE) cells caused OSE papillary hyperplasia but no tumors. Simultaneous
loss of Lkb1 and Pten lead to the development of ovarian serous cancer in 100%
animals (Lkb1ckoPtencko). Ovarian cancer in Lkb1ckoPtencko mice expressed typical
markers (WT1, Pax8, and ERĪ±) used for HOSC patients. Rapamycin, a well-known
inhibitor of mTOR, treatment suppressed OSE papillary hyperplasia and loss of either
TSC1 or TSC2 gene (Tuberous Sclerosis 1 and 2, upstream regulators of mTOR
signaling) phenocopies Lkb1cko phenotype. Collectively, we have shown importance
of LKB1-mTOR signaling in HOSC pathogenesis. Currently, we are conducting
preclinical trials using these mouse models and patient derived xenograft models to
develop better therapeutic treatments for human ovarian cancer patients.