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CD93 blockade overcomes sunitinib resistance in pancreatic neuroendocrine tumors
Yi Sun1, Yuki Fujiwara1, Robert J Torphy1
1Division of Surgical Oncology, Department of Surgery, the University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Abstract:
Pancreatic neuroendocrine tumors (PanNETs) are rare malignancies of the pancreas, but their incidence is steadily increasing. Standard therapy with antiangiogenic inhibitors, including sunitinib, has shown clinical benefit for advanced PanNETs; however, its long-term effectiveness is limited due to the development of resistance. In this study, we demonstrate that targeting the CD93-IGFBP7 axis enhances the efficacy of sunitinib by normalizing tumor vasculature in PanNETs. Both CD93 and its ligand IGFBP7 are enriched in the tumor microenvironment (TME) of PanNETs. Disrupting the CD93/IGFBP7 interaction with monoclonal antibodies (mAbs) in RIP1-Tag2 mice normalizes tumor vasculature to inhibit tumor progression and metastasis. Combining anti-CD93 mAb and sunitinib synergistically slows tumor growth and improves survival. Mechanistically, CD93 blockade mitigates sunitinib-induced tumor hypoxia and invasiveness, preventing the upregulation of proangiogenic factors. Critically, anti-CD93 mAb treatment prolongs survival in RIP1-Tag2 mice with late-stage, sunitinib-resistant PanNETs. Our results support CD93 blockade as a promising therapeutic approach for advanced PanNETs.
Insights
Targeting the CD93-IGFBP7 axis with antibodies can overcome resistance to sunitinib therapy in pancreatic neuroendocrine tumors (PanNETs). This approach normalizes tumor blood vessels, enhancing treatment efficacy and prolonging survival in advanced PanNETs.
Area of Science:
- Oncology
- Cancer Biology
- Immunotherapy
Background:
- Pancreatic neuroendocrine tumors (PanNETs) are rare but increasing malignancies.
- Sunitinib, an antiangiogenic inhibitor, shows benefit in advanced PanNETs but faces resistance.
- Tumor microenvironment (TME) factors like CD93 and IGFBP7 play roles in PanNET progression.
Purpose of the Study:
- To investigate the therapeutic potential of targeting the CD93-IGFBP7 axis in PanNETs.
- To evaluate the combination of anti-CD93 monoclonal antibodies (mAbs) and sunitinib.
- To understand the mechanisms by which CD93 blockade affects tumor vasculature and resistance.
Main Methods:
- Utilized the RIP1-Tag2 mouse model of PanNETs.
- Administered anti-CD93 mAbs alone and in combination with sunitinib.
- Assessed tumor vasculature normalization, progression, metastasis, hypoxia, and invasiveness.
- Monitored overall survival.
Main Results:
- Disrupting the CD93/IGFBP7 interaction normalized tumor vasculature, inhibiting PanNET progression and metastasis.
- Combination therapy synergistically slowed tumor growth and improved survival.
- CD93 blockade mitigated sunitinib-induced hypoxia and invasiveness.
- Anti-CD93 mAb treatment prolonged survival in late-stage, sunitinib-resistant PanNETs.
Conclusions:
- Targeting the CD93-IGFBP7 axis is a promising strategy to enhance sunitinib efficacy in PanNETs.
- CD93 blockade normalizes tumor vasculature, overcoming resistance mechanisms.
- This approach offers a potential new therapeutic avenue for advanced PanNETs.
