No abstract

J o u r n a l o f I n t e g r a t i v e N e u r o s c i e n c e

With the availability of gene expression data by RNA-seq, powerful statistical approaches for grouping similar gene expression profiles across different environments have become increasingly important. We describe and assess a computational model for clustering genes into distinct groups based on the pattern of gene expression in response to changing environment. The model capitalizes on the Poisson distribution to capture the count property of RNA-seq data. A two-stage hierarchical expectation–maximization (EM) algorithm is implemented to estimate an optimal number of groups and mean expression amounts of each group across two environments. A procedure is formulated to test whether and how a given group shows a plastic response to environmental changes. The impact of gene–environment interactions on the phenotypic plasticity of the organism can also be visualized and characterized. The model was used to analyse an RNA-seq dataset measured from two cell lines of breast cancer that respond differently to an anti-cancer drug, from which genes associated with the resistance and sensitivity of the cell lines are identified. We performed simulation studies to validate the statistical behaviour of the model. The model provides a useful tool for clustering gene expression data by RNA-seq, facilitating our understanding of gene functions and networks.

10505 Background: Activation of anaplastic lymphoma kinase has been detected in several pediatric malignancies, including anaplastic large-cell lymphoma (ALCL), inflammatory myofibroblastic tumor (IMT), neuroblastoma and others. Preliminary findings from this phase 1, multicenter, dose-escalation study (NCT01742286) indicated a Maximum Tolerated Dose (MTD)/Recommended Dose for Expansion (RDE) of the potent oral ALK inhibitor ceritinib to be 510 mg/m2 (fasted) and 500 mg/m2 (fed) in pediatric patients (pts). Here, we report final safety, pharmacokinetics (PK) and efficacy results. Methods: Children aged ≥1 to <18 years with advanced, mostly pretreated, ALK-aberrant malignancies were enrolled in this study. Dose escalation was conducted to determine the MTD/RDE of ceritinib (primary objective), in both fasted and fed states, following which pts entered an expansion phase to evaluate safety, tolerability, and efficacy at the MTD/RDE. Secondary objectives were evaluation of safety, PK, and efficacy (overall response rate [ORR], duration of response [DOR] and progression-free survival [PFS]). Results: A total of 83 pts (median age, 8 years) with ALK-aberrant malignancies were enrolled into dose-escalation (n = 40) and expansion (n = 43) study periods. Of these, 55 pts (neuroblastoma, n = 30; IMT, n = 10; ALCL, n = 8; others, n = 7) were treated with ceritinib at MTD/RDE (510 mg/m2 [fasted], n = 13; 500 mg/m2 [fed], n = 42). Systemic exposure of ceritinib between the two doses was comparable, so data were pooled for efficacy assessment. The ORRs (95% CI) were 75% (34.9-96.8) for pts with ALCL, 70% (34.8-93.3) for IMT and 20% (7.7-38.6) for neuroblastoma. The median DOR was 15 months (95% CI: 5.8, 22.2) for the 6/30 pts with neuroblastoma who had confirmed CR or PR treated at fasted/fed MTD/RDE. Median DOR was not reached for those with ALCL and IMT. Most common adverse events (AEs) (N = 83; all-grades, all-causality, ≥50% of pts): vomiting (86.7%), diarrhea (78.3%), increased ALT (65.1%), increased AST (59.0%), nausea (56.6%), and abdominal pain (50.6%). Grade 3/4 AEs were observed in 80.7% of pts (mostly transaminase elevations) and were manageable. Six pts (7.2%) were discontinued from ceritinib due to a grade 3/4 AE (mostly transaminase elevation). Conclusions: Substantial activity was observed with ceritinib at the RDE in pts with IMT, ALCL and heavily pretreated neuroblastoma. The toxicity profile of ceritinib in children was manageable and similar to that previously reported in adults. Clinical trial information: NCT01742286.