IGF system targeted therapy: Therapeutic opportunities for ovarian cancer

Abstract

The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential.

CA125 over‐release behavior following a 75‐g oral glucose test as a predictive biomarker of multidrug resistance in patients with ovarian cancer

“…Insulin (including IGF1/2) and its receptors (IR/IGF1R) are commonly expressed by human neoplasia and play a vital role in the whole body. 8,9 The data obtained from our proofof-principle experiments can be summarized in the following points: (1) CA125 synthesis/secretion is regulated by the IR-PI3K-Akt axis (Fig. 1); and (2) overexpression of IR or GLUT4 activates the PI3K-Akt axis, leading to chemoresistance and the over-release of CA125 (Fig.…”

“…Overexpression of IR or GLUT4 confers enhanced chemoresistance to ovarian cancer cells at physiological glucose and insulin levels IR-PI3K-Akt overactivation and GLUT4 overexpression are reportedly associated with ovarian cancer chemoresistance. [8][9][10][11]20 However, there is little evidence regarding the in vitro effects of IR and GLUT4 on the acquisition of multidrug resistance in ovarian cancer cells. Therefore, we constructed the recombinant lentiviruses Lenti-INSR and Lenti-SLC2A4 to investigate the chemoresistance-promoting roles of IR and GLUT4, respectively ( Fig.…”

“…Insulinrelated receptors, including insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) and their downstream effector, glucose transporter 4 (GLUT4), are highly expressed by ovarian cancer. [8][9][10] GLUT4 facilitates glucose entry into the cytoplasm, satisfying the requirements for adenosine triphosphate (ATP) supply and glycoprotein synthesis. 11 Insulin signals are transduced via the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) pathway, 8,9 which upregulates the antiapoptotic protein myeloid cell leukemia sequence (Mcl)-1 and downregulates proapoptotic proteins, such as p53, B-cell lymphoma-2-associated death promoter (Bad) and Caspase 9.…”

“…[8][9][10] GLUT4 facilitates glucose entry into the cytoplasm, satisfying the requirements for adenosine triphosphate (ATP) supply and glycoprotein synthesis. 11 Insulin signals are transduced via the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) pathway, 8,9 which upregulates the antiapoptotic protein myeloid cell leukemia sequence (Mcl)-1 and downregulates proapoptotic proteins, such as p53, B-cell lymphoma-2-associated death promoter (Bad) and Caspase 9. [12][13][14][15] In addition, this pathway is responsible for protein synthesis through phosphorylated ribosomal S6K1/2 proteins, 16 promoting the release of protumoral cytokines (e.g., interleukin 8, vascular endothelial growth factor, and urokinase-type plasminogen-activator).…”

“…[17][18][19] Genetic alterations that strengthen the activity of the PI3K-Akt pathway, e.g., PI3KCA mutation and phosphatase and tensin homolog (PTEN) copy number loss, are predominant mechanisms leading to multidrug (e.g., TP) resistance in ovarian cancer. 20 Despite the important roles of insulin and its receptors in contributing to chemoresistance, current techniques that can be used to noninvasively evaluate insulin (and/or IGF1/2, the ligands of IGF1R 8,9 )-dependent multidrug resistance are lacking. Nevertheless, as a recognized serum biomarker, the ovarian cancer-derived soluble protein CA125 has long been used to evaluate the efficacies of debulking surgery and chemotherapy.…”