1. Low Bcl-2 is a robust biomarker of sensitivity to nab-paclitaxel in Ewing sarcoma.
- Author
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Pascual-Pasto G, Resa-Pares C, Castillo-Ecija H, Aschero R, Baulenas-Farres M, Vila-Ubach M, Burgueño V, Balaguer-Lluna L, Cuadrado-Vilanova M, Olaciregui NG, Martinez-Velasco N, Perez-Jaume S, de Alava E, Tirado OM, Lavarino C, Mora J, and Carcaboso AM
- Subjects
- Child, Humans, Biomarkers, Osteonectin genetics, Osteonectin metabolism, Osteonectin therapeutic use, Paclitaxel pharmacology, Paclitaxel therapeutic use, Antineoplastic Agents therapeutic use, Bone Neoplasms drug therapy, Bone Neoplasms pathology, Rhabdomyosarcoma drug therapy, Sarcoma, Ewing drug therapy, Sarcoma, Ewing pathology
- Abstract
Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) shows potent preclinical anticancer activity in pediatric solid tumors such as Ewing sarcoma, rhabdomyosarcoma and neuroblastoma, but responses in clinical trials have been modest. In this work, we aimed to discover a rational biomarker-based approach to select the right candidate patients for this treatment. We assessed the efficacy of nab-paclitaxel in 27 patient-derived xenografts (PDX), including 14 Ewing sarcomas, five rhabdomyosarcomas and several other pediatric solid tumors. Response rate (partial or complete response) was remarkable in rhabdomyosarcomas (four of five) and Ewing sarcomas (four of 14). We addressed several predictive factors of response to nab-paclitaxel such as the expression of the secreted protein acidic and rich in cysteine (SPARC), chromosomal stability of cancer cells and expression of antiapoptotic members of the B-cell lymphoma-2 (Bcl-2) family of proteins such as Bcl-2, Bcl-xL, Bcl-W and Mcl-1. Protein (immunoblotting) and gene expression of SPARC correlated positively, while immunoblotting and immunohistochemistry expression of Bcl-2 correlated negatively with the efficacy of nab-paclitaxel in Ewing sarcoma PDX. The negative correlation of Bcl-2 immunoblotting signal and activity was especially robust (r = 0.8352; P = 0.0007; Pearson correlation). Consequently, we evaluated pharmacological strategies to inhibit Bcl-2 during nab-paclitaxel treatment. We observed that the Bcl-2 inhibitor venetoclax improved the activity of nab-paclitaxel in highly resistant Bcl-2-expressing Ewing sarcoma PDX. Overall, our results suggest that low Bcl-2 expression could be used to select patients with Ewing sarcoma sensitive to nab-paclitaxel, and Bcl-2 inhibitors could improve the activity of this drug in Bcl-2-expressing Ewing sarcoma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2023
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