Citations

Abstract Purpose: Trebananib is a first-in-class antiangiogenic peptibody (peptide–Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D), and pharmacokinetics (PK). Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15, or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI. Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia (n = 4), anemia, thrombocytopenia, neutropenia, vomiting, and hypertension (n = 1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI. Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg. Clin Cancer Res; 23(20); 6062–9. ©2017 AACR.

Tumor-initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals. Mechanistic investigations identified NFATc2 response elements in the 3’ enhancer region of SOX2, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5’ enhancer. Through this axis, oxidative stress induced by cancer drug treatment is attenuated, leading to increased resistance in a mutation-independent manner. Targeting this axis provides a novel approach for the long-term treatment of lung cancer through TIC elimination.

Abstract Purpose: Receptor tyrosine kinases (RTKs) are frequently deregulated in leukemia, yet the biological consequences of this deregulation remain elusive. The mechanisms underlying aberrant methylation, a hallmark of leukemia, are not fully understood. Here we investigated the role of RTKs in methylation abnormalities and characterized the hypomethylating activities of RTK inhibitors. Experimental Design: Whether and how RTKs regulate expression of DNA methyltransferases (DNMTs), tumor suppressor genes (TSGs) as well as global and gene-specific DNA methylation were examined. The pharmacologic activities and mechanisms of actions of RTK inhibitors in vitro, ex vivo, in mice, and in nilotinib-treated leukemia patients were determined. Results: Upregulation of RTKs paralleled DNMT overexpression in leukemia cell lines and patient blasts. Knockdown of RTKs disrupted, whereas enforced expression increased DNMT expression and DNA methylation. Treatment with the RTK inhibitor, nilotinib, resulted in a reduction of Sp1-dependent DNMT1 expression, the diminution of global DNA methylation, and the upregulation of the p15INK4B gene through promoter hypomethylation in AML cell lines and patient blasts. This led to disruption of AML cell clonogenicity and promotion of cellular apoptosis without obvious changes in cell cycle. Importantly, nilotinib administration in mice and human patients with AML impaired expression of DNMTs followed by DNA hypomethylation, TSG re-expression, and leukemia regression. Conclusions: Our findings demonstrate RTKs as novel regulators of DNMT-dependent DNA methylation and define DNA methylation status in AML cells as a pharmacodynamic marker for their response to RTK-based therapy, providing new therapeutic avenues for RTK inhibitors in overcoming epigenetic abnormalities in leukemia. Clin Cancer Res; 23(20); 6254–66. ©2017 AACR.

Significance Deposition of amyloid-β (Aβ) peptide in the form of parenchymal plaques and Aβ accumulation in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA) are pathological hallmarks of Alzheimer’s disease (AD). The clusterin ( CLU ) gene, which confers AD risk, is associated with amyloid deposition. Here we show that loss of CLU promotes cerebrovascular CAA, yet significantly reduces the amount of parenchymal plaques by altering perivascular drainage of Aβ in the APP/PS1 mouse model of AD. The absence of CLU in these mice is associated with a lower number of hemorrhages and a decrease in inflammation. These results suggest that CLU functions as a major Aβ chaperone to maintain Aβ solubility along interstitial fluid drainage pathways and prevent CAA formation.

AbstractBackgroundIn treatment planning for intensity‐modulated proton therapy (IMPT), we aim to deliver the prescribed dose to the target yet minimize the dose to adjacent healthy tissue. Mixed‐integer programming (MIP) has been applied in radiation therapy to generate treatment plans. However, MIP has not been used effectively for IMPT treatment planning with dose‐volume constraints. In this study, we incorporated dose‐volume constraints in an MIP model to generate treatment plans for IMPT.MethodsWe created a new MIP model for IMPT with dose volume constraints. Two groups of IMPT treatment plans were generated for each of three patients by using MIP models for a total of six plans: one plan was derived with the Limited‐memory Broyden–Fletcher–Goldfarb–Shanno (L‐BFGS) method while the other plan was derived with our MIP model with dose‐volume constraints. We then compared these two plans by dose‐volume histogram (DVH) indices to evaluate the performance of the new MIP model with dose‐volume constraints. In addition, we developed a model to more efficiently find the best balance between tumor coverage and normal tissue protection.ResultsThe MIP model with dose‐volume constraints generates IMPT treatment plans with comparable target dose coverage, target dose homogeneity, and the maximum dose to organs at risk (OARs) compared to treatment plans from the conventional quadratic programming method without any tedious trial‐and‐error process. Some notable reduction in the mean doses of OARs is observed.ConclusionsThe treatment plans from our MIP model with dose‐volume constraints can meet all dose‐volume constraints for OARs and targets without any tedious trial‐and‐error process. This model has the potential to automatically generate IMPT plans with consistent plan quality among different treatment planners and across institutions and better protection for important parallel OARs in an effective way.

PurposeTo implement and evaluate a novel and fast method for proton range verification by using a planar scintillator and step wedge.MethodsA homogenous proton pencil beam plan with 35 energies was designed and delivered to a 2D flat scintillator with a step wedge. The measurement was repeated 15 times (3 different days, 5 times per day). The scintillator image was smoothed, the Bragg peak and distal fall off regions were fitted by an analytical equation, and the proton range was calculated using simple trigonometry. The accuracy of this method was verified by comparing the measured ranges to those obtained using an ionization chamber and a scanning water tank, the gold standard. The reproducibility was evaluated by comparing the ranges over 15 repeated measurements. The sensitivity was evaluated by delivering to same beam to the system with a film inserted under the wedge.ResultsThe range accuracy of all 35 proton energies measured over 3 days was within 0.2 mm. The reproducibility in 15 repeated measurements for all 35 proton ranges was ±0.045 mm. The sensitivity to range variation is 0.1 mm for the worst case. This efficient procedure permits measurement of 35 proton ranges in less than 3 min. The automated data processing produces results immediately. The setup of this system took less than 5 min. The time saving by this new method is about two orders of magnitude when compared with the time for water tank range measurements.ConclusionsA novel method using a scintillator with a step wedge to measure the proton range was implemented and evaluated. This novel method is fast and sensitive, and the proton range measured by this method was accurate and highly reproducible.