PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG.

• Keywords
• PDGFRA alteration, PDGFRA amplification, PDGFRA inhibitor, PDGFRA mutation, avapritinib, brain penetrance, diffuse midline glioma, glioblastoma, high-grade glioma, tyrosine kinase inhibitor,
• MeSH
• Child MeSH
• Adult MeSH
• Glioma * drug therapy   genetics   pathology   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Protein Kinase Inhibitors * pharmacology   therapeutic use   MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Brain Neoplasms * drug therapy   genetics   pathology   MeSH
• Child, Preschool MeSH
• Antineoplastic Agents * pharmacology   therapeutic use   MeSH
• Pyrazoles * pharmacology   therapeutic use   MeSH
• Receptor, Platelet-Derived Growth Factor alpha * genetics   antagonists & inhibitors   metabolism   MeSH
• Neoplasm Grading MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Mice MeSH
• Child, Preschool MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• avapritinib MeSH Browser
• Protein Kinase Inhibitors * MeSH
• Antineoplastic Agents * MeSH
• Pyrazoles * MeSH
• Pyrroles MeSH
• Receptor, Platelet-Derived Growth Factor alpha * MeSH
• Triazines MeSH

Tyrosine kinase inhibitors (TKIs) are frequently used in combined therapy to enhance treatment efficacy and overcome drug resistance. The present study analyzed the effects of three inhibitors, sunitinib, gefitinib, and lapatinib, combined with iron-chelating agents, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) or di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). Simultaneous administration of the drugs consistently resulted in synergistic and/or additive activities against the cell lines derived from the most frequent types of pediatric solid tumors. The results of a detailed analysis of cell signaling in the neuroblastoma cell lines revealed that TKIs inhibited the phosphorylation of the corresponding receptor tyrosine kinases, and thiosemicarbazones downregulated the expression of epidermal growth factor receptor, platelet-derived growth factor receptor, and insulin-like growth factor-1 receptor, leading to a strong induction of apoptosis. Marked upregulation of the metastasis suppressor N-myc downstream regulated gene-1 (NDRG1), which is known to be activated and upregulated by thiosemicarbazones in adult cancers, was also detected in thiosemicarbazone-treated neuroblastoma cells. Importantly, these effects were more pronounced in the cells treated with drug combinations, especially with the combinations of lapatinib with thiosemicarbazones. Therefore, these results provide a rationale for novel strategies combining iron-chelating agents with TKIs in therapy of pediatric solid tumors.

• Keywords
• NDRG1, neuroblastoma, pediatric solid tumors, receptor tyrosine kinases, thiosemicarbazones, tyrosine kinase inhibitors,
• Publication type
• Journal Article MeSH

Despite constant advances in the field of pediatric oncology, the survival rate of high-risk neuroblastoma patients remains poor. The molecular and genetic features of neuroblastoma, such as MYCN amplification and stemness status, have established themselves not only as potent prognostic and predictive factors but also as intriguing targets for personalized therapy. Novel thiosemicarbazones target both total level and activity of a number of proteins involved in some of the most important signaling pathways in neuroblastoma. In this study, we found that di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) potently decreases N-MYC in MYCN-amplified and c-MYC in MYCN-nonamplified neuroblastoma cell lines. Furthermore, DpC succeeded in downregulating total EGFR and phosphorylation of its most prominent tyrosine residues through the involvement of NDRG1, a positive prognostic marker in neuroblastoma, which was markedly upregulated after thiosemicarbazone treatment. These findings could provide useful knowledge for the treatment of MYC-driven neuroblastomas that are unresponsive to conventional therapies.

• Keywords
• DpC, EGFR, MYC, NDRG1, lipid droplet, neuroblastoma, thiosemicarbazone,
• MeSH
• Gene Amplification drug effects   MeSH
• Models, Biological MeSH
• Iron Chelating Agents pharmacology   MeSH
• Down-Regulation drug effects   MeSH
• ErbB Receptors metabolism   MeSH
• Phosphorylation drug effects   MeSH
• Stress, Physiological drug effects   MeSH
• Intracellular Signaling Peptides and Proteins metabolism   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Neuroblastoma metabolism   pathology   MeSH
• Cell Cycle Proteins metabolism   MeSH
• N-Myc Proto-Oncogene Protein metabolism   MeSH
• Proto-Oncogene Proteins c-akt metabolism   MeSH
• Pyridines pharmacology   MeSH
• Signal Transduction * MeSH
• Thiosemicarbazones pharmacology   MeSH
• Cell Shape drug effects   MeSH
• Gene Silencing drug effects   MeSH
• Up-Regulation drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Iron Chelating Agents MeSH
• di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone MeSH Browser
• ErbB Receptors MeSH
• Intracellular Signaling Peptides and Proteins MeSH
• N-myc downstream-regulated gene 1 protein MeSH Browser
• Cell Cycle Proteins MeSH
• N-Myc Proto-Oncogene Protein MeSH
• Proto-Oncogene Proteins c-akt MeSH
• Pyridines MeSH
• Thiosemicarbazones MeSH

Giant-cell tumor of bone (GCTB) is an intermediate type of primary bone tumor characterized by locally aggressive growth with metastatic potential. The aim of this study was to identify new druggable targets among the cell signaling molecules involved in GCTB tumorigenesis. Profiles of activated signaling proteins in fresh-frozen tumor samples and tumor-derived cell lines were determined using phosphoprotein arrays. Analysis of the obtained data revealed epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor beta (PDGFRβ) as potential targets, but only the PDGFR inhibitor sunitinib caused a considerable decrease in stromal cell viability in vitro. Furthermore, in the case of a 17-year-old patient suffering from GCTB, we showed that the addition of sunitinib to the standard treatment of GCTB with the monoclonal antibody denosumab resulted in the complete depletion of multinucleated giant cells and mononuclear stromal cells in the tumor tissue. To summarize, the obtained data showed that a specific receptor tyrosine kinase (RTK) signaling pattern is activated in GCTB cells and plays an important role in the regulation of cell proliferation. Thus, activated RTKs and their downstream signaling pathways represent useful targets for precision treatment with low-molecular-weight inhibitors or with other types of modern biological therapy.

• Keywords
• PDGFR beta, denosumab, giant-cell tumor of bone, signaling, sunitinib, targeted treatment,
• Publication type
• Journal Article MeSH