Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.

Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m2/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib's rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

Thermal Microelectromechanical Sensor Construction

The problem of constructing a thermal sensor based on the technology of microelectromechanical systems is solved by structural and circuit integration of capacitance-dependent and thermomechanical parts. For this, the use of a MOS transistor (capacitance-dependent part) with a gate in the form of a bimorph membrane (thermomechanical part), which performs cyclic oscillations under the influence of heating from a sensitive element and subsequent cooling, is proposed. The novelty of the proposed sensor is the provision of a frequency-dependent output signal without the use of additional generator circuits. This makes it easier to combine the sensor with digital signal processing systems and reduce the influence of transmission lines on measurement accuracy. Also, the advantages of the sensor include reduced overall dimensions, which is achieved due to the vertical integration of its elements.Model studies of the sensor are carried out and on their basis circuit and software-hardware solutions for determining the temperature of the sensitive element are proposed. It is shown that the use of logarithmic dependence to approximate the influence of the temperature of the sensitive element on the output pulse frequency of the sensor minimizes the measurement error to 3.08 %. The composition of the information and measurement system, which contains a thermal sensor, a sensor signal pre-processing circuit and measurement processing unit using the Atmega328 microcontroller on the platform of the unified ArduinoUno module, is determined. It is shown that the total error of temperature determination in the developed system does not exceed 4.18 % in the temperature range of the sensor element from 20 °C to 47 °C.The program code for the microcontroller part of the information and measurement system is developed, which occupies 12 % of the program memory and 4.9 % of the dynamic memory of the unified module.The proposed thermal microelectromechanical sensor can be used for contact measurement of the temperature of gaseous and liquid media, recording of optical radiation and microwave signal

The p53 activator overcomes resistance to ALK inhibitors by regulating p53-target selectivity in ALK-driven neuroblastomas

Abstract Anaplastic lymphoma kinase (ALK) is an oncogenic receptor tyrosine kinase that is activated by gene amplification and mutation in neuroblastomas. ALK inhibitors can delay the progression of ALK-driven cancers, but are of limited use owing to ALK inhibitor resistance. Here, we show that resistance to ALK inhibitor in ALK-driven neuroblastomas can be attenuated by combination treatment with a p53 activator. Either ALK inhibition or p53 activator treatment induced cell cycle arrest, whereas combination treatment induced apoptosis, and prevented tumour relapse both in vitro and in vivo. This shift toward apoptosis, and away from cell-cycle arrest, in the presence of an ALK inhibitor and a p53 activator, is mediated by inhibition of the ALK–AKT–FOXO3a axis leading to a specific upregulation of SOX4. SOX4 cooperates with p53 to upregulate the pro-apoptotic protein PUMA. These data therefore suggest a novel combination therapy strategy for treating ALK-driven neuroblastomas

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)—many of which are refractory to current standard-of-care treatments—from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer