Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma.

Background: Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets. Methods: Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG. Surgical biopsies were performed after enrollment and prior to definitive treatment. All subjects were treated with conventional external beam radiotherapy with bevacizumab, and then stratified to receive bevacizumab with erlotinib or temozolomide, both agents, or neither agent, based on O6-methylguanine-DNA methyltransferase status and epidermal growth factor receptor expression. Whole-genome sequencing and RNA sequencing were performed but not used for treatment assignment. Results: Fifty-three patients were enrolled at 23 institutions, and 50 underwent biopsy. The median age was 6.4 years, with 24 male and 29 female subjects. Surgical biopsies were performed with a specified technique and no deaths were attributed to the procedure. Two subjects experienced grade 3 toxicities during the procedure (apnea, n = 1; hypertension, n = 1). One subject experienced a neurologic deficit (left hemiparesis) that did not fully recover. Of the 50 tumors biopsied, 46 provided sufficient tissue to perform the study assays (92%, two-stage exact binomial 90% CI: 83%-97%). Conclusions: Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions.

Classification of treatment-related mortality in children with cancer: a systematic assessment.

Treatment-related mortality is an important outcome in paediatric cancer clinical trials. An international group of experts in supportive care in paediatric cancer developed a consensus-based definition of treatment-related mortality and a cause-of-death attribution system. The reliability and validity of the system was tested in 30 deaths, which were independently assessed by two clinical research associates and two paediatric oncologists. We defined treatment-related mortality as death occurring in the absence of progressive cancer. Of the 30 reviewed deaths, the reliability of classification for treatment-related mortality was noted as excellent by clinical research associates (κ=0·83, 95% CI 0·60-1·00) and paediatric oncologists (0·84, 0·63-1·00). Criterion validity was established because agreement between the consensus classifications by clinical research associates and paediatric oncologists was almost perfect (0·92, 0·78-1·00). Our approach should allow comparison of treatment-related mortality across trials and across time.

Profiling pathway-specific novel therapeutics in preclinical assessment for central nervous system atypical teratoid rhabdoid tumors (CNS ATRT): favorable activity of targeting EGFR- ErbB2 signaling with lapatinib.

Despite intensifying multimodal treatments, children with central nervous system atypical teratoid/rhabdoid tumor (CNS ATRT) continue to endure unacceptably high mortality rates. At present, concerted efforts are focusing on understanding the characteristic INI1 mutation and its implications for the growth and survival of these tumors. Additionally, pharmaceutical pipeline libraries constitute a significant source of potential agents that can be taken to clinical trials in a timely manner. However, this process requires efficient target validation and relevant preclinical studies. As an initial screening approach, a panel of 129 small molecule inhibitors from multiple pharmaceutical pipeline libraries was tested against three ATRT cell lines by in vitro cytotoxicity assays. Based on these data, agents that have strong activity and corresponding susceptible cellular pathways were identified. Target modulation, antibody array analysis, drug combination and in vivo xenograft studies were performed on one of the pathway inhibitors found in this screening. Approximately 20% of agents in the library showed activity with IC(50) values of 1 µM or less and many showed IC(50) values less than 0.05 µM. Intra cell line variability was also noted among some of the drugs. However, it was determined that agents capable of affecting pathways constituting ErbB2, mTOR, proteasomes, Hsp90, Polo like kinases and Aurora kinases were universally effective against the three ATRT cell lines. The first target selected for further analysis, the inhibition of ErbB2-EGFR pathway by the small molecule inhibitor lapatinib, indicated inhibition of cell migration properties and the initiation of apoptosis. Synergy between lapatinib and IGF-IR inhibition was also demonstrated by combination index (CI) values. Xenograft studies showed effective antitumor activity of lapatinib in vivo. We present an experimental approach to identifying agents and drug combinations for future clinical trials and provide evidence for the potential of lapatinib as an effective agent in the context of the biology and heterogeneity of its targets in ATRT.