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CD99 triggering in Ewing sarcoma delivers a lethal signal through p53 pathway reactivation and cooperates with
Clara Guerzoni1, Valentina Fiori2, Mario Terracciano3
1CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna, Italy. PROMETEO Laboratory, STB, RIT Department, Istituto Ortopedico Rizzoli, Bologna, Italy.
Purpose:
The paucity of new drugs for the treatment of Ewing sarcoma (EWS) limits the cure of these patients. CD99 has a strong membranous expression in EWS cells and, being also necessary for tumor survival, is a suitable target to aim at. In this article, we described a novel human monospecific bivalent single-chain fragment variable diabody (dAbd C7) directed against CD99 of potential clinical application.
Experimental Design:
In vitro and in vivo evaluation of cell death and of the molecular mechanisms triggered by anti-CD99 agents were performed alone or in combination with doxorubicin to demonstrate efficacy and selectivity of the new dAbd C7.
Results:
The dAbd C7 induced rapid and massive EWS cell death through Mdm2 degradation and p53 reactivation. Mdm2 overexpression as well as silencing of p53 in p53wt EWS cells decreased CD99-induced EWS cell death, whereas treatment with nutlin-3 enhanced it. Furthermore, cell death was associated with induction of p21, bax, and mitochondrial depolarization together with substantial inhibition of tumor cell proliferation. Combined treatment of anti-CD99 dAbd C7 with doxorubicin was additive both in vitro and in vivo against EWS xenografts. Normal mesenchymal stem cells showed no p53 activation and were resistant to cell death, unless transformed by EWS-FLI, the oncogenic driver of EWS.
Conclusions:
These results indicate that dAbd C7 is a suitable candidate tool to target CD99 in patients with EWS able to spare normal stem cells from death as it needs an aberrant genetic context for the efficient delivery of CD99-triggered cell death.
Insights
A novel diabody targeting CD99 effectively eliminates Ewing sarcoma (EWS) cells by reactivating p53. This new therapy spares normal stem cells, offering a promising treatment for EWS patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Ewing sarcoma (EWS) treatment options are limited due to a lack of new drugs.
- CD99 is highly expressed on EWS cells and is crucial for tumor survival, making it a viable therapeutic target.
Purpose of the Study:
- To develop and evaluate a novel human monospecific bivalent single-chain fragment variable diabody (dAbd C7) targeting CD99 for potential clinical application in EWS treatment.
Main Methods:
- In vitro and in vivo studies assessed cell death and molecular mechanisms induced by anti-CD99 agents, alone and with doxorubicin.
- Evaluated the efficacy and selectivity of the dAbd C7 diabody.
Main Results:
- dAbd C7 induced rapid EWS cell death via Mdm2 degradation and p53 reactivation.
- Cell death involved p21 induction, bax, mitochondrial depolarization, and proliferation inhibition.
- Combined dAbd C7 and doxorubicin showed additive efficacy against EWS xenografts.
- Normal stem cells were resistant to dAbd C7 unless transformed by EWS-FLI.
Conclusions:
- dAbd C7 is a promising therapeutic candidate for targeting CD99 in EWS.
- The diabody effectively triggers cell death in EWS cells while sparing normal stem cells.
- Its efficacy relies on the aberrant genetic context specific to EWS.
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