Inactivation of SMC2 shows a synergistic lethal response in MYCN-amplified neuroblastoma cells.

The condensin complex is required for chromosome condensation during mitosis; however, the role of this complex during interphase is unclear. Neuroblastoma is the most common extracranial solid tumor of childhood, and it is often lethal. In human neuroblastoma, MYCN gene amplification is correlated with poor prognosis.

Integrating cell-based and clinical genome-wide studies to identify genetic variants contributing to treatment failure in neuroblastoma patients.

High-risk neuroblastoma is an aggressive malignancy, with high rates of treatment failure. We evaluated genetic variants associated with in vitro sensitivity to two derivatives of cyclophosphamide for association with clinical response in a separate replication cohort of neuroblastoma patients (n = 2,709). To determine sensitivity, lymphoblastoid cell lines (LCLs) were exposed to increasing concentrations of 4-hydroperoxycyclophosphamide (4HC; n = 422) and phosphoramide mustard (PM; n = 428).

Time to disease progression in children with relapsed or refractory neuroblastoma treated with ABT-751: a report from the Children's Oncology Group (ANBL0621).

Background: ABT-751, an orally bioavailable sulfonamide binds the colchicine site of beta-tubulin and inhibits microtubule polymerization. Prior phase I studies established the recommended dose in children with solid tumors as 200 mg/m(2) PO daily × 7 days every 21 days and subjects with neuroblastoma experienced prolonged stable disease. We conducted a phase 2 study (NCT00436852) in children and adolescents with progressive neuroblastoma to determine if ABT-751 prolonged the time to progression (TTP) compared to a hypothesized standard based on a historical control population.

Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma.

Purpose: Neuroblastoma is a pediatric cancer that continues to exact significant morbidity and mortality. Recently, a number of cell-cycle proteins, particularly those within the Cyclin D/CDK4/CDK6/RB network, have been shown to exert oncogenic roles in neuroblastoma, suggesting that their therapeutic exploitation might improve patient outcomes.

Experimental Procedures: We evaluated the effect of dual CDK4/CDK6 inhibition on neuroblastoma viability using LEE011 (Novartis Oncology), a highly specific CDK4/6 inhibitor.

Initial testing (stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program.

Background: Quisinostat (JNJ-26481585) is a second-generation pyrimidyl-hydroxamic acid histone deacetylase (HDAC) inhibitor with high cellular potency towards Class I and II HDACs. Quisinostat was selected for clinical development as it showed prolonged pharmacodynamic effects in vivo and demonstrated improved single agent antitumoral efficacy compared to other analogs.

Procedures: Quisinostat was tested against the PPTP in vitro panel at concentrations ranging from 1.

Initial testing (Stage 1) of TAK-701, a humanized hepatocyte growth factor binding antibody, by the Pediatric Preclinical Testing Program.

TAK-701 is a humanized antibody that binds hepatocyte growth factor (HGF), thus suppressing c-Met transduced signaling and c-Met dependent proliferation and migration of tumor cells. Six childhood solid tumor xenografts were selected for evaluating TAK-701 based on immunochemical detection of HGF/c-Met autocrine signaling [i.e.

Initial testing (stage 1) of the Polo-like kinase inhibitor volasertib (BI 6727), by the Pediatric Preclinical Testing Program.

Background: Volasertib (BI 6727) is a potent inhibitor of Polo-like kinase 1 (Plk1), that is overexpressed in several childhood cancers and cell lines. Because of its novel mechanism of action, volasertib was evaluated through the PPTP.

Procedures: Volasertib was tested against the PPTP in vitro cell line panel at concentrations from 0.

Neuroblastoma of undifferentiated subtype, prognostic significance of prominent nucleolar formation, and MYC/MYCN protein expression: a report from the Children's Oncology Group.

Background: This study sought to investigate biological/clinicopathological characteristics of neuroblastoma, undifferentiated subtype (NBUD).

Methods: This study examined 157 NBUD cases filed at the Children's Oncology Group Neuroblastoma Pathology Reference Laboratory, and survival rates of the patients were analyzed with known prognostic factors. Immunostainings for MYCN and MYC protein were performed on 68 tumors.

Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial.

Background: Myeloablative chemoradiotherapy and immunomagnetically purged autologous bone marrow transplantation has been shown to improve outcome for patients with high-risk neuroblastoma. Currently, peripheral blood stem cells (PBSC) are infused after myeloablative therapy, but the effect of purging is unknown. We did a randomised study of tumour-selective PBSC purging in stem-cell transplantation for patients with high-risk neuroblastoma.

ERBB3 is a marker of a ganglioneuroblastoma/ganglioneuroma-like expression profile in neuroblastic tumours.

Background: Neuroblastoma (NB) tumours are commonly divided into three cytogenetic subgroups. However, by unsupervised principal components analysis of gene expression profiles we recently identified four distinct subgroups, r1-r4. In the current study we characterized these different subgroups in more detail, with a specific focus on the fourth divergent tumour subgroup (r4).

Phase I trial of fenretinide delivered orally in a novel organized lipid complex in patients with relapsed/refractory neuroblastoma: a report from the New Approaches to Neuroblastoma Therapy (NANT) consortium.

Background: A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4-HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma.

Procedure: 4-HPR/LXS powder (352-2,210 mg/m(2) /day) was administered on Days 0-6, in 21-day courses, by standard 3 + 3 design.

Results: Thirty-two patients (median age = 8 years, range 3-27 years) enrolled with 30 evaluable for dose escalation.

Spatial disaggregation of tick occurrence and ecology at a local scale as a preliminary step for spatial surveillance of tick-borne diseases: general framework and health implications in Belgium.

Background: The incidence of tick-borne diseases is increasing in Europe. Sub national information on tick distribution, ecology and vector status is often lacking. However, precise location of infection risk can lead to better targeted prevention measures, surveillance and control.

Initial testing (Stage 1) of the antibody-maytansinoid conjugate, IMGN901 (Lorvotuzumab mertansine), by the pediatric preclinical testing program.

Background: IMGN901 (lorvotuzumab mertansine) is an antibody-drug conjugate composed of a humanized antibody that specifically binds to CD56 (NCAM, neural cell adhesion molecule) and that is conjugated to the maytansinoid, DM1 (a microtubule targeting agent).

Procedures: IMGN901 and DM1-SMe (unconjugated DM1 as a mixed disulfide with thiomethane to cap its sulfhydryl group) were tested in vitro at concentrations ranging from 0.01 nM to 0.

Proton versus photon radiation therapy for patients with high-risk neuroblastoma: the need for a customized approach.

Background: Proton therapy for treatment for high-risk neuroblastoma may offer sparing of organs at risk (OAR) when compared to intensity-modulated X-ray therapy (IMXT).

Procedure: Double-scattered proton plans and IMXT plans delivering 2,160 cGy to the primary tumor site and other residual disease were developed for 13 consecutive HR-NBL patients. Radiation doses to target volumes and OAR were calculated to determine the optimal modality for each.

Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study.

Background: Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma.

Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program.

Background: Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers.

Procedures: Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.

Targeting MYCN: a good BET for improving neuroblastoma therapy?

Direct targeting of oncogenic MYC proteins has been an elusive goal of many cancer drug development efforts. In this issue of Cancer Discovery, Stegmaier and colleagues demonstrate that pharmacologically interfering with the bromodomain and extraterminal (BET) class of proteins potently depletes MYCN in neuroblastoma cells, resulting in cellular cytotoxicity and thus providing a novel approach with a potential impact on a previously undruggable major oncogene.

Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children's oncology group.

Unlabelled: Radiolabeled metaiodobenzylguanidine (mIBG) is a highly sensitive and specific marker for detecting neuroblastoma. A semiquantitative mIBG score (Curie score [CS]) was assessed for utility as a prognostic indicator for a cohort of patients with high-risk metastatic disease.

Methods: mIBG scans from 280 patients with mIBG-avid, stage 4 neuroblastoma enrolled on the Children's Oncology Group (COG) protocol A3973 were evaluated at diagnosis (n = 280), after induction chemotherapy (n = 237), and after an autologous stem cell transplantation (n = 178).

Initial testing (stage 1) of temozolomide by the pediatric preclinical testing program.

Background: The DNA methylating agent temozolomide was developed primarily for treatment of glioblastoma. However, preclinical data have suggested a broader application for treatment of childhood cancer. Temozolomide was tested against the PPTP solid tumor and ALL models.

The genetic landscape of high-risk neuroblastoma.

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.

A pilot study of tandem high-dose chemotherapy with stem cell rescue as consolidation for high-risk neuroblastoma: Children's Oncology Group study ANBL00P1.

Increasing treatment intensity has improved outcomes for children with neuroblastoma. We performed a pilot study in the Children's Oncology Group to assess the feasibility and toxicity of a tandem myeloablative regimen without TBI supported by autologous CD34-selected peripheral blood stem cells. Forty-one patients with high-risk neuroblastoma were enrolled; eight patients did not receive any myeloablative consolidation procedure and seven received only one.

Initial testing (stage 1) of ganetespib, an Hsp90 inhibitor, by the Pediatric Preclinical Testing Program.

Ganetespib, an Hsp90 inhibitor, was tested against the PPTP in vitro cell line panel and selected xenografts in vivo, including JAK2- and BRAF-mutated models. Ganetespib demonstrated potent in vitro cytotoxic activity (median rIC50 8.8 nM, range 4.

Children's Oncology Group's 2013 blueprint for research: neuroblastoma.

Estimated 5-year survival rates for patients with non-high-risk and high-risk neuroblastoma are 90% and 50%, respectively. Recent clinical trials have shown excellent outcomes with reduced therapy for non-high-risk disease. For patients with high-risk neuroblastoma treated with chemoradiotherapy, surgery, and stem cell transplantation, the addition of anti-disialoganglioside (GD2) immunotherapy plus cytokines improves survival.

Trans-population analysis of genetic mechanisms of ethnic disparities in neuroblastoma survival.

Background: Black patients with neuroblastoma have a higher prevalence of high-risk disease and worse outcome than white patients. We sought to investigate the relationship between genetic variation and the disparities in survival observed in neuroblastoma.

Methods: The analytic cohort was composed of 2709 patients.