EphB4/EphrinB2 therapeutics in Rhabdomyosarcoma.

Matthew E Randolph,Zia Bajwa,Pali Kaur,Valery Krasnoperov,Matthew N Svalina,Parkash Gill,Joel E Michalek,Sunny Xiang,Carol J Bult,Michael C Young,James Keck,Megan M Cleary,Atiya Mansoor,Martin W Goros,Charles Keller,Qiang Wang

doi:10.1371/journal.pone.0183161

Matthew E Randolph, Zia Bajwa + Show 14 more

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https://doi.org/10.1371/journal.pone.0183161

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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.

Highlights

Rhabdomyosarcoma (RMS) is a highly aggressive tumor with myogenic features and ranks as the most common soft tissue cancer in children
Ephrin receptor B4 (EphB4) receptor tyrosine kinase signaling has been associated with oncogenic Pax3: Foxo1 fusion protein expression and involved in alveolar rhabdomyosarcoma (aRMS) tumor progression [9]
We utilized several in vivo mouse models of both alveolar and embryonal RMS to test the effectiveness of solely targeting the EphB4/EphrinB2 pathway as a potential therapeutic for childhood RMS

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Introduction

Rhabdomyosarcoma (RMS) is a highly aggressive tumor with myogenic features and ranks as the most common soft tissue cancer in children. RMS poses significant challenges to treatment because more than half of tumors metastasize early in the disease [1]. Metastatic forms of the two most common subtypes of RMS, alveolar and embryonal, are associated with especially poor clinical outcomes [1, 2]. Long-term survival rates of children with rhabdomyosarcoma have not improved in over thirty years, with survival rates of 40% for embryonal rhabdomyosarcoma (eRMS) and less than 20% for alveolar rhabdomyosarcoma (aRMS) [2, 3]. New therapeutic targets that address tumor invasion and metastasis are urgently needed to improve patient outcomes.

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