Insulin-Like Growth Factor Signaling as a Therapeutic Target in Pancreatic Cancer

Abstract

Insulin-like growth factor-1 (IGF-1) leads via its receptor IGF-1R to the activation of the PI3K/Akt pathway, providing antiapoptotic signals to pre-malignant and malignant cells. In pancreatic cancer, IGF-1 and its receptor are constitutively overexpressed. Mammalian target of rapamycin (mTOR) is the main mediator of mitogenic stimuli transduced by PI3K/Akt. Interestingly, inhibition of mTOR activates PI3K/Akt by up-regulating IGF-1R signaling. Several targeted agents have been developed to inhibit the activity of IGF-1 or to block IGF-1R. These pharmaceuticals may offer additional ways of stimulating apoptosis in neoplastic cells. Yet, there are difficulties in targeting this pathway: The ideal anti-cancer drug target is expressed only in cancer cells; however, IGF-1 and its receptor IGF-1R are ubiquitously expressed throughout the body. Moreover, when using antibodies against IGF-1R, the structurally similar insulin receptor might also be blocked, leading to hyperglycemia as a severe side effect. There are currently several phase I/II trials investigating IGF-1 and its receptor as a drug target in various kinds of cancer. Specifically, therapeutic effects on pancreatic cancer by combining a humanized monoclonal antibody against IGF-1R with other chemotherapeutics are being investigated. To improve the clinical outcome of mTOR inhibitors such as everolimus, it has been suggested to use combination therapies of mTOR inhibitors and IGF-1/IGF-1R inhibitors. In theory, this would counterbalance the feedback effects of mTOR inhibition on IGF-1 signaling. In conclusion, IGF-1 and its receptor are promising new drug targets in cancer therapy. Combination therapies of IGF-1/IGF-1R inhibitors and mTOR inhibitors could improve the clinical outcome.

New insights into pancreatic cancer stem cells

“…Multiple pathways that contribute to the CSC properties of DCLK1HI/AcTubHI pancreatic cancer cells were identified by using whole genome transcriptome analysis [6] . Studies identified ABL1 and IGF1R to be highly expressed in DCLK1HI/AcTubHI cells, complementing ongoing preclinical and clinical evaluation of ABL1 and IGF1R pathway inhibition as new forms of targeted therapy for pancreatic cancer [38,39] . These studies suggest that both invasive and preinvasive PC may depend on DCLK1 expressing cells with cancer stem cell capabilities.…”

“…Earlier studies have suggested that Dclk1 may mark tumor-initiating cells in a variety of tumor types [27][28][29][30][31][32][33][34][35][36][37][38][39] . DclK1 regulates several key oncogenes like c-MYC, KRAS, NOTCH1 and EMT [32,33,39] .…”

The Prolyl Peptidases PRCP/PREP Regulate IRS-1 Stability Critical for Rapamycin-induced Feedback Activation of PI3K and AKT

“…The PI3K/AKT pathway is activated by RTKs e.g. IR/IGF-1R which are involved in the development of different cancers including cancer of pancreas (5,15,26). AKT activates mTOR that further phosphorylates its downstream targets ribosomal protein p70 S6 kinase (S6K1) and initiation factor 4E-binding protein-1 (4E-BP1) to control transcription and translation (2,35,36).…”

“…Current targeted therapeutics have very limited effect on pancreatic cancer patients (9,(12)(13)(14). Past research has linked insulin and IGF signaling to the tumorigenesis and progression of pancreatic cancer (15,16). The PI3K/AKT/mTOR pathway is downstream of IR/IGF-1R and is associated with development and clinical aggressiveness of pancreatic cancer (17)(18)(19)(20).…”

Co-expression of FOXL1 and PP2A inhibits proliferation inducing apoptosis in pancreatic cancer cells via promoting TRAIL and reducing phosphorylated MYC

“…However, except erlotinib, which is an inhibitor to epidermal growth factor receptor (EGFR), no other targeted therapy has as yet demonstrated significant effect against pancreatic cancer (9,10). Insulin-like growth factor 1 (IGF-1) and its receptor, PI3-kinase/Akt/mTOR and mitogen-activated protein kinases/extracellular signal-regulated kinases (MEK/ERK) pathway are upregulated in the majority of PDACs (11,12). However, a phase II trial on a monoclonal antibody against IGF receptor (IGFR) indicates no significant effect in OS and progression-free survival (PFS) for PDAC patients (4).…”