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Background: The KDM1A histone demethylase regulates the cellular balance between proliferation and differentiation, and is often deregulated in human cancers including the childhood tumor neuroblastoma. We previously showed that KDM1A is strongly expressed in undifferentiated neuroblastomas and correlates with poor patient prognosis, suggesting a possible clinical benefit from targeting KDM1A. Methods: Here, we tested the efficacy of NCL-1, a small molecule specifically inhibiting KDM1A in preclinical models for neuroblastoma. Results: NCL-1 mimicked the effects of siRNA-mediated KDM1A knockdown and effectively inhibited KDM1A activity in four neuroblastoma cell lines and a patient-representative cell model. KDM1A inhibition shifted the aggressive tumor cell phenotypes towards less aggressive phenotypes. The proliferation and cell viability was reduced, accompanied by the induction of markers of neuronal differentiation. Interventional NCL-1 treatment of nude mice harboring established neuroblastoma xenograft tumors reduced tumor growth and inhibited cell proliferation. Reduced vessel density and defects in blood vessel construction also resulted, and NCL-1 inhibited the growth and tube formation of HUVEC-C cells in vitro. Conclusions : Inhibiting KDM1A could attack aggressive neuroblastomas two-fold, by re-directing tumor cells toward a less aggressive, slower-growing phenotype and by preventing or reducing the vascular support of large tumors.

Background/Objectives : Integrating the cytotoxic drug busulfan into a high-dose chemotherapy regimen prior to autologous hematopoietic stem cell rescue in patients with high-risk neuroblastoma has improved the survival of children battling this deadly disease. Busulfan-induced toxicities can, however, be severe. Here, we describe the diagnosis and successful treatment of acute pulmonary injury by total-body-weight-adjusted busulfan therapy in two children with high-risk neuroblastoma. Case series : Patient 1 developed life-threatening biphasic acute respiratory failure on days +60 and +100 after busulfan therapy, requiring intubation and invasive mechanical ventilation. Despite intensive anti-inflammatory and immunomodulatory therapy, including systemic corticosteroids, topical inhalation regimens, azithromycin, nintedanib and extracorporal photopheresis, patient 1 required extended intensive care measures and non-invasive respiratory support for a total of 20 months. High-resolution computed tomography showed diffuse intra-alveolar and interstitial patterns. Patient 2 developed partial respiratory failure with insufficient oxygen saturation and dyspnea on day +52 after busulfan therapy. Symptoms were resolved after 6 months of systemic corticosteroids, topical inhalation regimens and azithromycin. High-resolution computed tomography showed atypical pneumonic changes with ground-glass opacities. While both patients fully recovered without evidence of pulmonary fibrosis, cancer therapy had to be paused and then modified until full recovery from busulfan-induced lung injury. Conclusions : Busulfan-induced lung injury requires prompt diagnosis and intervention. Symptoms and signs are nonspecific and difficult to differentiate from other causes. Therapeutic busulfan drug level monitoring and the identification of patients at risk for drug overdosing through promoter polymorphisms in the glutathione S-transferase alpha 1 gene encoding the main enzyme in busulfan metabolism are expected to reduce the risk of busulfan-induced toxicities.