EphB4/EphrinB2 therapeutics in Rhabdomyosarcoma
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Published on: May 3, 2021
Matthew E Randolph1, Megan M Cleary1,2, Zia Bajwa1
1Children's Cancer Therapy Development Institute, Beaverton, Oregon, United States of America.
Abstract:
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma affecting children and is often diagnosed with concurrent metastases. Unfortunately, few effective therapies have been discovered that improve the long-term survival rate for children with metastatic disease. Here we determined effectiveness of targeting the receptor tyrosine kinase, EphB4, in both alveolar and embryonal RMS either directly through the inhibitory antibody, VasG3, or indirectly by blocking both forward and reverse signaling of EphB4 binding to EphrinB2, cognate ligand of EphB4. Clinically, EphB4 expression in eRMS was correlated with longer survival. Experimentally, inhibition of EphB4 with VasG3 in both aRMS and eRMS orthotopic xenograft and allograft models failed to alter tumor progression. Inhibition of EphB4 forward signaling using soluble EphB4 protein fused with murine serum albumin failed to affect eRMS model tumor progression, but did moderately slow progression in murine aRMS. We conclude that inhibition of EphB4 signaling with these agents is not a viable monotherapy for rhabdomyosarcoma.
Insights
Targeting EphB4 receptor tyrosine kinase showed limited effectiveness for treating pediatric rhabdomyosarcoma (RMS). Therapies inhibiting EphB4 signaling did not significantly improve tumor progression in preclinical models, indicating it
Area of Science:
- Oncology
- Molecular Biology
- Pediatric Cancer Research
Background:
- Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, frequently presenting with metastases.
- Current therapies offer limited improvement in long-term survival for metastatic RMS.
- EphB4 receptor tyrosine kinase is a potential therapeutic target in RMS.
Purpose of the Study:
- To evaluate the efficacy of targeting EphB4 in alveolar (aRMS) and embryonal (eRMS) rhabdomyosarcoma.
- To assess direct inhibition via antibody VasG3 and indirect blockade of EphB4/EphrinB2 signaling.
Main Methods:
- Utilized orthotopic xenograft and allograft models for aRMS and eRMS.
- Administered inhibitory antibody VasG3 targeting EphB4.
- Tested soluble EphB4-murine serum albumin fusion protein to block forward signaling.
Main Results:
- EphB4 expression in eRMS correlated with longer patient survival.
- VasG3 treatment did not alter tumor progression in aRMS or eRMS models.
- Soluble EphB4 partially slowed progression in aRMS but not eRMS models.
Conclusions:
- Direct or indirect inhibition of EphB4 signaling is not a viable monotherapy for rhabdomyosarcoma.
- Further research is needed to identify effective therapeutic strategies for pediatric RMS.
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