Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to
Lukas J A C Hawinkels1, Amaya Garcia de Vinuesa2, Madelon Paauwe1
1Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, the Netherlands. Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
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. An immunohistochemical 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.
Insights
New antiangiogenic therapy targeting bone morphogenetic protein (BMP)9/activin receptor-like kinase (ALK)1 signaling showed promise. Combining ALK1-Fc with chemotherapy enhanced anti-tumor effects, suggesting a new clinical strategy for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Anti-VEGF antiangiogenic therapy is widely used but often encounters resistance.
- Novel antiangiogenic strategies are crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To investigate the therapeutic potential of targeting the bone morphogenetic protein (BMP)9/activin receptor-like kinase (ALK)1 signaling pathway.
- To evaluate the antiangiogenic and antitumor effects of ALK1-Fc protein, alone and in combination with chemotherapy.
Main Methods:
- In vivo studies using mouse models of melanoma, head and neck cancer, and invasive lobular breast carcinomas.
- ALK1-Fc protein was used to sequester BMP9 and BMP10, inhibiting their binding to ALK1.
- Assessed effects on tumor microvascular density, pericyte coverage, hypoxia, and tumor volume.
Main Results:
- ALK1-Fc treatment significantly reduced tumor microvascular density but did not decrease tumor volume as monotherapy.
- ALK1-Fc increased pericyte coverage and reduced hypoxia in tumors.
- Combination therapy with ALK1-Fc and cisplatin demonstrated superior tumor growth inhibition in breast and head and neck cancer models.
Conclusions:
- ALK1-Fc enhances the cytotoxic effects of chemotherapy, particularly cisplatin.
- Targeting ALK1 in combination with chemotherapy presents a strong rationale for clinical exploration.
- Results support further investigation in ongoing phase II clinical trials.
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