Targeting insulin and insulin-like growth factor pathways in epithelial ovarian cancer

Abstract

Ovarian cancer is the most lethal of all gynecological malignancies, due in part to the diagnosis at an advanced stage caused by the lack of specific signs and symptoms and the absence of reliable tests for screening and early detection. Most patients will respond initially to treatment but about 70% of them will suffer a recurrence. Therefore, new therapeutic modalities are urgently needed to overcome chemoresistance observed in ovarian cancer patients. Evidence accumulates suggesting that the insulin/insulin growth factor (IGF) pathways could act as a good therapeutic target in several cancers, including ovarian cancer. In this paper, we will focus on the role of insulin/IGF in ovarian cancer tumorigenesis and treatment.

Figure 1

IR and IGF family signaling pathway. Upon the binding of the ligand, the activated receptor will undergo autophosphorylation and in turn will phosphorylate IRS and SHC. Activated IRS will recruit GRB to the phosphorylated form of SHC adaptor protein. The SHC-GRB complex will induce RAS and turn on the MAPK/ERK pathway, inducing cell proliferation and survival. Phospho-IRS will also stimulate the PI3 kinase to phosphorylate AKT thus initiating its downstream effectors such as mTOR, promoting translation, proliferation, and cell survival. Generally, activated AKT will have an inhibitory effect on TSC2, allowing Rheb-GDP to be converted to its GTP-bound state, thereby activating mTOR and its downstream signaling molecules to promote cellular translation. Three different potential targeted therapies are underway of investigation in ovarian cancer, including IGF-IR antibodies, IGF-IR kinase inhibitors, and AMPK activators such as metformin.