Results of screening in early and advanced thoracic malignancies in the EORTC pan-European SPECTAlung platform.

Access to a comprehensive molecular alteration screening is patchy in Europe and quality of the molecular analysis varies. SPECTAlung was created in 2015 as a pan-European screening platform for patients with thoracic malignancies. Here we report the results of almost 4 years of prospective molecular screening of patients with thoracic malignancies, in terms of quality of the program and molecular alterations identified. Patients with thoracic malignancies at any stage of disease were recruited in SPECTAlung, from June 2015 to May 2019, in 7 different countries. Molecular tumour boards were organised monthly to discuss patients' molecular and clinical profile and possible biomarker-driven treatments, including clinical trial options. FFPE material was collected and analysed for 576 patients with diagnosis of pleural, lung, or thymic malignancies. Ultimately, 539 patients were eligible (93.6%) and 528 patients were assessable (91.7%). The turn-around time for report generation and molecular tumour board was 214 days (median). Targetable molecular alterations were observed in almost 20% of cases, but treatment adaptation was low (3% of patients). SPECTAlung showed the feasibility of a pan-European screening platform. One fifth of the patients had a targetable molecular alteration. Some operational issues were discovered and adapted to improve efficiency.

A transatlantic perspective on the integration of immuno-oncology prognostic and predictive biomarkers in innovative clinical trial design.

Immuno-therapeutics aim to activate the body's own immune system against cancer and are one of the most promising cancer treatment strategies, but currently limited by a variable response rate. Biomarkers may help to distinguish those patients most likely to respond to therapy; they may also help guide clinical decision making for combination therapies, dosing schedules, and determining progression versus relapse. However, there is a need to confirm such biomarkers in preferably prospective clinical trials before they can be used in practice. Accordingly, it is essential that clinical trials for immuno-therapeutics incorporate biomarkers. Here, focusing on the specific setting of immune therapies, we discuss both the scientific and logistical hurdles to identifying potential biomarkers and testing them in clinical trials.

Control of glioma cell death and differentiation by PKM2-Oct4 interaction.

Glioma stem cells are highly resistant to cell death and as such are supposed to contribute to tumor recurrence by eluding anticancer treatments. Here, we show that spheroids that contain rat neural stem cells (NSCs) or rat glioma stem cells (cancer stem cells, CSCs) express isoforms 1 and 2 of pyruvate kinase (PKM1 and PKM2); however, the expression of PKM2 is considerably higher in glioma spheroids. Silencing of PKM2 enhances both apoptosis and differentiation of rat and human glioma spheroids. We establish that PKM2 was implicated in glioma spheroid differentiation through its interaction with Oct4, a major regulator of self-renewal and differentiation in stem cells. The small molecule Dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, increases the amount of PKM2/Oct4 complexes and thus inhibited Oct4-dependent gene expression. Taken together, our results highlight a new molecular pathway through which PKM2 can manage gliomagenesis via the control of glioma stemness by Oct4.

Deriving therapies for children with primary CNS tumors using pharmacokinetic modeling and simulation of cerebral microdialysis data.

The treatment of children with primary central nervous system (CNS) tumors continues to be a challenge despite recent advances in technology and diagnostics. In this overview, we describe our approach for identifying and evaluating active anticancer drugs through a process that enables rational translation from the lab to the clinic. The preclinical approach we discuss uses tumor subgroup-specific models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder researchers in this field. This approach involves performing extensive systemic (plasma) and target site (CNS tumor) pharmacokinetic studies. Pharmacokinetic modeling and simulation of the data derived from these studies are then used to inform future decisions regarding drug administration, including dosage and schedule. Here, we also present how our approach was used to examine two FDA approved drugs, simvastatin and pemetrexed, as candidates for new therapies for pediatric CNS tumors. We determined that due to unfavorable pharmacokinetic characteristics and insufficient concentrations in tumor tissue in a mouse model of ependymoma, simvastatin would not be efficacious in further preclinical trials. In contrast to simvastatin, pemetrexed was advanced to preclinical efficacy studies after our studies determined that plasma exposures were similar to those in humans treated at similar tolerable dosages and adequate unbound concentrations were found in tumor tissue of medulloblastoma-bearing mice. Generally speaking, the high clinical failure rates for CNS drug candidates can be partially explained by the fact that therapies are often moved into clinical trials without extensive and rational preclinical studies to optimize the transition. Our approach addresses this limitation by using pharmacokinetic and pharmacodynamic modeling of data generated from appropriate in vivo models to support the rational testing and usage of innovative therapies in children with CNS tumors.