Immunoliposome for Ewing Sarcoma.

Abstract

Background/aim: Metastatic Ewing sarcoma (EWS) causes high mortality. Precision medicine can help to mitigate dismal outcomes by targeted and more effective eradication of cancer cells. The aim of the study was to propose a targeted immunoliposome (IL) that has a potential of selectively binding to and destroying EWS cells. EWS expresses CD99 used for diagnostics. If CD99 is used for targeted IL, its payload must be more damaging to EWS than normal cells, which may also express CD99. Poly(ADP-ribose) polymerase (PARP) inhibitors are potential payload candidates, since they may enhance apoptosis of EWS-cells treated with DNA-damaging agents.

Materials and methods: The R2 genomics platform was used to explore the differential expression of CD99 and PARP1 in seven different databases (two EWS and five various normal tissues). Kaplan-Meier analysis was conducted for prognostic significance of PARP1 expression. The side-effect profile of PARP inhibitors allowed selection of a potential payload for proposed IL.

Results: EWS samples (Savola/Surdez, n=196) had higher CD99 expression than 737 normal tissues. Endothelial compartment had twice-higher CD99 compared to other normal tissues but lower CD99 and PARP1 than EWS. Recurrent/metastatic EWS expressed more PARP1 than primary tumors (ANOVA p=0.02, Savola). Ten-year survival respectively for low versus high PARP1 expression was 36% vs. 14% for EFS (p=0.016), and 50% vs. 7% for OS (p<0.001). Normal hematopoietic/B-cell compartments had ≥2-times higher PARP1 than other tissues; therefore, niraparib (least lymphotoxic of PARP inhibitors), was favored as a payload for anti-EWS IL.

Conclusion: Immunoliposomes covered with anti-CD99 mAbs and loaded with small-molecule niraparib may be developed as an adjuvant therapy for advanced EWS. Projected 100 nm IL should provide vascular permeability and tumor tropism; however, extensive preclinical evaluations will also be required regarding hematopoietic and endothelial damage.