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Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen‐rich gas (MV‐O 2 ). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF‐Rα gene in preterms with nCLD and directly test the effect of PDGF‐Rα haploinsufficiency on the development of nCLD using a preclinical mouse model of MV‐O 2 . In the context of MV‐O 2 , attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF‐Rα‐dependent reduction in lung VEGF‐A. TGF‐β contributes to the PDGF‐Rα‐dependent decrease in myofibroblast function. Remarkably, endotracheal treatment with exogenous PDGF‐A rescues both the lung defects in haploinsufficient mice undergoing MV‐O 2 . Overall, our results establish attenuated PDGF signaling as an important driver of nCLD pathology with provision of PDGF‐A as a protective strategy for newborns undergoing MV‐O 2 . Synopsis A genetic approach in a neonatal mouse ventilation model shows that PDGFRA haploinsufficiency is sufficient to produce neonatal chronic lung disease (nCLD)‐like pathology, and that therapeutic ligand provision can rescue these defects. Mechanical ventilation with oxygen‐rich gas (MV‐O 2 ) results in attenuated signaling via PDGFRA in myofibroblasts in part due to an effect of TGF‐β, resulting in impaired secondary septation and reduced expression of VEGF‐A with increased endothelial cell apoptosis, cardinal features of nCLD. PDGFRA‐haploinsufficiency in mice confers enhanced susceptibility to development of nCLD with MV‐O 2 , which can be rescued by endotracheal provision of exogenous PDGF. Human preterm infants with nCLD show significant enrichment for SNPs in the PDGFRA gene associated with reduced protein level expression of PDGFRA and impaired lung myofibroblast activity. Graphical Abstract A genetic approach in a neonatal mouse ventilation model shows that PDGFRA haploinsufficiency is sufficient to produce neonatal chronic lung disease (nCLD)‐like pathology, and that therapeutic ligand provision can rescue these defects.

Melanomas have a high potential to metastasize to the brain. Recent advances in targeted therapies and immunotherapies have changed the therapeutical landscape of extracranial melanomas. However, few patients with melanoma brain metastasis (MBM) respond effectively to these treatments and new therapeutic strategies are needed. Cabozantinib is a receptor tyrosine kinase (RTK) inhibitor, already approved for the treatment of non-skin-related cancers. The drug targets several of the proteins that are known to be dysregulated in melanomas. The anti-tumor activity of cabozantinib was investigated using three human MBM cell lines. Cabozantinib treatment decreased the viability of all cell lines both when grown in monolayer cultures and as tumor spheroids. The in vitro cell migration was also inhibited and apoptosis was induced by cabozantinib. The phosphorylated RTKs p-PDGF-Rα, p-IGF-1R, p-MERTK and p-DDR1 were found to be downregulated in the p-RTK array of the MBM cells after cabozantinib treatment. Western blot validated these results and showed that cabozantinib treatment inhibited p-Akt and p-MEK 1/2. Further investigations are warranted to elucidate the therapeutic potential of cabozantinib for patients with MBM.

To investigate the possible role of imatinib, an inhibitor of the tyrosine kinase activity of PDGF-R, in desmoplastic small round cell tumor (DSRCT). From August 2005 to June 2009, DSRCT patients refractory to conventional treatment were enrolled. Patients received imatinib 400 mg daily. Primary end point of this open label, prospective, Phase II trial was objective response rate. Of the 13 enrolled patients, eight were evaluable for response. Median age was 20 years (range: 9-32). Objective responses at 3 months were: stable disease in one patient and progressive disease in seven patients. Imatinib showed no efficacy in the treatment of DSRCT unresponsive to conventional therapy, despite molecular-based selection of patients.

Gastrointestinal stromal tumours (GISTs), the most common mesenchymal tumours of the digestive tract, are largely resistant to chemo- and radiotherapy. They are currently defined by their overexpression of the KIT receptor tyrosine kinase (CD117), a member of the family of receptor tyrosine kinases (RTKs), and exhibit KIT mutations in more than 85% of cases. Additionally, in more than one-third of KIT wild-type GISTs, mutations of platelet-derived growth factor receptor alpha (PDGF-R alpha), which also belongs to the family of RTKs, were recently found. Since these data indicate that uncontrolled RTK signalling may be implicated in the pathogenesis of GISTs, RTKs and the activated downstream signalling cascades are attractive targets in the therapy of these tumours. Imatinib is a small-molecule inhibitor that selectively blocks the activity of the PDGF-R, ABL and KIT receptor tyrosine kinases by competitive binding to the adenosine triphosphate binding site of their catalytic domains. We herein review the molecular pathological, preclinical and clinical data that identify imatinib as a valuable new agent in the treatment of GISTs.