Abstract
Purpose :
IGF-1 plays a major role in tumor cell proliferation and survival, and its receptor, IGF-1R, plays a significant role in multi-step process of cancer metastasis. Here, we investigated whether the IGF-1/IGF-1R signaling axis is involved in UM growth and metastasis. We also attempted targeting this signaling pathway with a small molecule inhibitor of Insulin Receptor Substrates 1/2 (IRS1/2), the first downstream effectors of IGF-1R activation.
Methods :
We analyzed TCGA datasets for determining IGF-1R and IRS-1 expression in UM primary tumors and analyzed IRS-1 protein levels immunohistochemically in matched eye and liver UM tumors. We also compared IGF-1R expression in normal (non-cancer) vs. UM cells. We then investigated the potential of NT157, a small molecule inhibitor of IRS-1/2 in blocking IGF-1/IGF-1R signaling in UM cells as well as UM tumors in a chicken egg chorioallantoic membrane (CAM) model, and subcutaneous (subQ) UM tumors in mice. We used reverse phase protein array (RPPA) analysis to identify global proteomic changes with NT157 treatment. We also compared the effectiveness of a neutralizing monoclonal IGF-1R antibody versus NT157 in blocking UM cell survival and migration.
Results :
TCGA dataset analysis reveals that UM has high IGF-1R and IRS-1 expression and IGF-1R is over-expressed in all UM cell lines tested relative to non -cancer/normal cells. High IRS-1 expression was detected in the matched eye and liver UM tumors. On using NT157 to inhibit IRS1/2, we observed reduction in UM cell survival, migration and apoptosis induction in vitro. More significantly, NT157 blocked UM tumor growth in a CAM model, and in a mouse subQ model validating the in vitro effect. From our experiments comparing NT157 with a monoclonal antibody to IGF-1R, we found NT157 to be more effective in blocking IGF-1R signaling in UM. RPPA analysis detected significant proteomic changes in the PI3K/AKT pathway with NT157 treatment.
Conclusions :
Together, these results suggest that IGF-1/IGF-1R signaling plays a significant role in UM cell and tumor growth. Our results also show that the IRS1/2 inhibitor, NT157, inhibits UM cell survival, migration in vitro and tumor growth in vivo.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.