Abstract A014: IGFBP-3 Neutralization Promotes Tumor Angiogenesis In a Murine Model Of PDAC
Zachary Sechrist, Nidhi Patel, Gary Hannon, Scott Gerber, Calvin ColeAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related death and has a 5-year survival rate of just 13%. Poor survival rates are attributable in part to treatment intolerance of the tumor burden caused by high stromal density, limited chemotherapy delivery, and a hypovascular tumor microenvironment. Recent studies have linked increased tumor vascularization with improved survival, underscoring the need to study therapies that regulate angiogenesis. Our laboratory previously showed that PDAC tumors express insulin-like growth factor binding protein-3 (IGFBP-3), a regulator of angiogenesis. Targeted deletion of the IGFBP-3 (IGFBP-3-/-) gene in PDAC tumor cells improved overall survival and slowed tumor growth at the median timepoint. However, at the end of life no difference was observed in tumor size or igfbp3 expression compared to parental tumors. Preliminary single-cell sequencing data shows that endothelial cells secrete a significantly higher levels of IGFBP-3 compared to other cells in the tumor microenvironment except for tumor cells, providing a possible explanation for the increased angiogenesis and IGFBP-3 expression seen in IGFBP-3-/- tumors. Here, we investigate the role of tumor-derived IGFBP-3 in angiogenesis and evaluate anti-IGFBP-3 as a regulator of angiogenesis in vitro.
Methods:
Female C57BL/6J mice (6–8 weeks) were randomized to receive orthotopic injections of KP2-Luc parental or IGFBP-3-/- KP2-Luc cells (n=10/group). At sacrifice, tumors were collected, sectioned, and stained for Factor VIII+ endothelial cells. Angiogenesis was evaluated in vitro using propidium iodide proliferation, Matrigel tube formation, and transwell migration assays with murine SVEC4-10 cells. SVEC4-10 cells were treated with conditioned media (CM) from KP2 parental cells ± 5 µg/mL anti-IGFBP-3 NmAb or CM from IGFBP-3-/- cells. ImageJ was used to quantify vascular network formation and cell migration.
Results:
Interestingly, at end-of-life IGFBP-3-/- tumors exhibited a significant increase in the number and maturity of Factor VIII+ endothelial cells (p<0.01) suggesting that loss of IGFBP-3 expression in tumor cell promotes angiogenesis. As such murine SVEC4-10 cells were subject to treatment with parental or IGFBP-3-/- CM to test proliferation, vasculogenesis, and migration. Surprisingly, no difference was observed in endothelial cell proliferation, but there was a significant increase in tube formation over and an increase in endothelial cell migration following treatment with IGFBP-3-/- CM (p<0.05). Excitingly, anti-IGFBP-3 NmAb treatment promoted tube formation in SVEC4-10 cells compared to KP2 parental CM alone (p<0.05).
Conclusions:
These findings suggest that targeting tumor-derived IGFBP-3 may increase tumor vascularization, reduce tumor growth, and enhance drug delivery in PDAC. Future studies will examine temporal changes in tumor vasculature following IGFBP-3 neutralization and evaluate anti-IGFBP-3 NmAb as an adjuvant to chemotherapy.
Citation Format:
Zachary Sechrist, Nidhi Patel, Gary Hannon, Scott Gerber, Calvin Cole. IGFBP-3 Neutralization Promotes Tumor Angiogenesis In a Murine Model Of PDAC [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A014.