Fratini, L. | bioRxiv Science

bioRxiv2025

Delayed growth of Ewing sarcoma tumors associated with reduced expression and activity of Trk receptors, PI3K, and IGF1R

Ewing sarcoma (ES) is an aggressive childhood tumor. We have previously shown that tropomyosin receptor kinase (Trk) neurotrophin receptors regulate viability, and the pan-Trk and kinase inhibitor K252a restores sensitivity to chemotherapy, in ES cells. Here, we show that administration of K252a in mice delays ES tumor growth and reduces expression and activity of multiple targets. BALB/c nu/nu nude mice inoculated with SK-ES-1 ES cells were given daily intraperitoneal (i.p.) injections of K252a for 18 days. Immunohistochemical analysis of tumors was performed to quantify the expression and phosphorylation of Trk receptors, phosphoinositide 3-kinase (PI3K), and insulin-like growth factor 1 receptor (IGF1R). Associations between genes encoding Trks, PI3G, and IGF1R and overall survival (OS) in patients with ES was examined. Treatment with K252a led to a transient delay in ES tumor growth and reduced the expression and phosphorylation of TrkA, TrkB, PI3K, and IGF1R. Combined treatment with K252a and the IGF1R inhibitor NVP-ADW742 was more effective in reducing ES cell viability than each compound alone. Significant associations between expression of NTRK genes and patient OS were found, indicating that NTRK genes should be further evaluated as biomarkers for prognosis in patients with ES.

cancer biology↗

bioRxiv2023

Modulation of Viability, Proliferation, and Stemness by Rosmarinic Acid in Medulloblastoma Cells: Involvement of HDACs and EGFR

Medulloblastoma (MB) is a heterogeneous group of malignant pediatric brain tumors, divided into molecular groups with distinct biological features and prognosis. Currently available therapy often results in poor long-term quality of life for patients, which will be afflicted by neurological, neuropsychiatric, and emotional sequelae. Identifying novel therapeutic agents capable of targeting the tumors without jeopardizing patients quality of life is imperative. Rosmarinic acid (RA) is a plant-derived compound whose action against a series of diseases including cancer has been investigated, with no side effects reported so far. Previous studies have not examined whether RA has effects in MB. Here, we show RA is cytotoxic against human Daoy (IC50= 168 M) and D283 (IC50= 334 M) MB cells. Exposure to RA for 48 h reduced histone deacetylase 1 (HDAC1) expression while increasing H3K9 hyperacetylation, reduced epidermal growth factor (EGFR) expression, and inhibited EGFR downstream targets extracellular-regulated kinase (ERK)1/2 and AKT in Daoy cells. These modifications were accompanied by increased expression of CDKN1A/p21, reduced expression of SOX2, and a decrease in proliferative rate. Treatment with RA also reduced cancer stem cell markers expression and neurosphere size. Taken together, our findings indicate that RA can reduce cell proliferation and stemness and induce cell cycle arrest in MB cells. Mechanisms mediating these effects may include targeting HDAC1, EGFR, and ERK signaling, and promoting p21 expression, possibly through an increase in H3K9ac and AKT deactivation. RA should be further investigated as a potential anticancer agent in experimental MB.

cancer biology↗