Journal
CLINICAL CANCER RESEARCH
Volume 22, Issue 1, Pages 96-106Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-15-0743
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Funding
- Dutch Cancer Society [UL2012-5459]
- Ludwig Institute for Cancer Research
- Swedisch Cancerfunden
- Netherlands Organization for Scientific Research (ZonMW-NWO)
- Centre for Biomedical Genetics
- Cancer Genomics Centre Netherlands
- LeDucq foundation grant
- Netherlands Institute for Regenerative Medicine (NIRM)
- EU
- Dutch Arthritis Association Reumafonds grant
- Dutch Cancer Society/Alpe d'huZes Bas Mulder award [UL2011 5051]
- ReumaFonds [14-2-404] Funding Source: researchfish
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Purpose: Antiangiogenic therapy, mostly targeting VEGF, has been applied in cancer patients for the last decade. However, resistance to anti-VEGF therapy and/or no significant benefit as monotherapeutic agent is often observed. Therefore, new antiangiogenic strategies are needed. In the current study, we investigated the therapeutic effect of interfering with the bone morphogenetic protein (BMP)9/activin receptor-like kinase (ALK)1 signaling pathway by using an ALK1-Fc ligand trap. Experimental Design: We analyzed the potential antiangiogenic and antitumor effects of ALK1-Fc protein as monotherapy and in combination with chemotherapy in vivo in mouse models of melanoma, head and neck cancer, and invasive lobular breast carcinomas. ALK1-Fc sequesters BMP9 and 10 and prevents binding of these ligands to endothelial ALK1, which regulates angiogenesis. Results: Treatment of mice with ALK1-Fc strongly decreased the tumors' microvascular density in the three different mouse cancer models. However, this effect was not accompanied by a reduction in tumor volume. Animmunohistochemical analysis of the tumor samples revealed that ALK1-Fc treatment increased the pericyte coverage of the remaining tumor vessels and decreased the hypoxia within the tumor. Next, we observed that combining ALK1-Fc with cisplatin inhibited tumor growth in the breast and head and neck cancer models more efficiently than chemotherapy alone. Conclusions: The addition of ALK1-Fc to the cisplatin treatment was able to enhance the cytotoxic effect of the chemotherapy. Our results provide strong rationale to explore combined targeting of ALK1 with chemotherapy in a clinical setting, especially in the ongoing phase II clinical trials with ALK1-Fc. (C)2015 AACR.
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