Growth exponents reflect evolutionary processes and treatment response in brain metastases.

Tumor growth is the result of the interplay of complex biological processes in huge numbers of individual cells living in changing environments. Effective simple mathematical laws have been shown to describe tumor growth in vitro, or simple animal models with bounded-growth dynamics accurately. However, results for the growth of human cancers in patients are scarce. Our study mined a large dataset of 1133 brain metastases (BMs) with longitudinal imaging follow-up to find growth laws for untreated BMs and recurrent treated BMs. Untreated BMs showed high growth exponents, most likely related to the underlying evolutionary dynamics, with experimental tumors in mice resembling accurately the disease. Recurrent BMs growth exponents were smaller, most probably due to a reduction in tumor heterogeneity after treatment, which may limit the tumor evolutionary capabilities. In silico simulations using a stochastic discrete mesoscopic model with basic evolutionary dynamics led to results in line with the observed data.

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism.

Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.

A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis.

We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.

NOX4 regulates TGFß-induced proliferation and self-renewal in glioblastoma stem cells.

Glioblastoma (GBM) is the most aggressive and common glioma subtype, with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy; thus, more effective approaches are needed. The glioblastoma tumoural mass is characterised by a small cellular subpopulation - glioblastoma stem cells (GSCs) - that has been held responsible for glioblastoma initiation, cell invasion, proliferation, relapse and resistance to chemo- and radiotherapy. Targeted therapies against GSCs are crucial, as is understanding the molecular mechanisms that govern the GSCs. Transforming growth factor ß (TGFß) signalling and reactive oxygen species (ROS) production are known to govern and regulate cancer stem cell biology. Among the differentially expressed genes regulated by TGFß in a transcriptomic analysis of two different patient-derived GSCs, we found NADPH oxidase 4 (NOX4) as one of the top upregulated genes. Interestingly, when patient tissues were analysed, NOX4 expression was found to be higher in GSCs versus differentiated cells. A functional analysis of the role of NOX4 downstream of TGFß in several patient-derived GSCs showed that TGFß does indeed induce NOX4 expression and increases ROS production in a NOX4-dependent manner. NOX4 downstream of TGFß regulates GSC proliferation, and NOX4 expression is necessary for TGFß-induced expression of stem cell markers and of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), which in turn controls the cell's antioxidant and metabolic responses. Interestingly, overexpression of NOX4 recapitulates the effects induced by TGFß in GSCs: enhanced proliferation, stemness and NRF2 expression. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology.

Universal scaling laws rule explosive growth in human cancers.

Most physical and other natural systems are complex entities composed of a large number of interacting individual elements. It is a surprising fact that they often obey the so-called scaling laws relating an observable quantity with a measure of the size of the system. Here we describe the discovery of universal superlinear metabolic scaling laws in human cancers. This dependence underpins increasing tumour aggressiveness, due to evolutionary dynamics, which leads to an explosive growth as the disease progresses. We validated this dynamic using longitudinal volumetric data of different histologies from large cohorts of cancer patients. To explain our observations we put forward increasingly-complex biologically-inspired mathematical models that captured the key processes governing tumor growth. Our models predicted that the emergence of superlinear allometric scaling laws is an inherently three-dimensional phenomenon. Moreover, the scaling laws thereby identified allowed us to define a set of metabolic metrics with prognostic value, thus providing added clinical utility to the base findings.

Vascular co-option in brain metastasis.

Vascular co-option by brain metastasis-initiating cells has been demonstrated as a critical step in organ colonization. The physical interaction between the cancer cell and the endothelial cell is mediated by integrins and L1CAM and could be involved in aggressive growth but also latency and immune evasion. The key involvement of vascular co-option in brain metastasis has created an emerging field that aims to identify critical targets as well as effective inhibitors with the goal of preventing brain metastases.

¿Qué se puede hacer en un área sanitaria para mejorar el control del gasto farmacéutico? / What can be done in a health care area to improve the control of drug costs?

El presente trabajo describe las actividades realizadas en el control del gasto farmacéutico en un área sanitaria (área 2 de Madrid). Se plantearon tres líneas de trabajo: a) definir sobre qué grupos de medicación actuar en función de su impacto económico, b) definir con qué intervenciones actuar en función de la evidencia existente y aplicarlas y c) iniciar un proceso de gestión del cambio, detectando resistencias y dificultades. Para la primera línea se plantearon alternativas, basándose en la evidencia, para los fármacos más prescritos, determinándose la parte del gasto que se habría evitado en el caso de aplicar la alternativa. En varios grupos de medicamentos se precisó realizar estudios de utilización. En la segunda línea de trabajo se realizó una revisión bibliográfica y una valoración crítica de la evidencia hallada. Para la tercera línea se formó un grupo de representantes de cada equipo de Atención Primaria (EAP) y se realizaron entrevistas a los líderes clínicos de los EAP. Resultados: a) Fármacos sobre los que actuar. Se seleccionaron los siguientes cambios (todos se refieren a aquellas situaciones en que el cambio está indicado): inhibidores de la enzima de conversión de la angiotensina (IECA) y antagonistas del calcio (ACA) por diuréticos, antagonistas de los receptores de angiotensina II (ARA II) por IECA, retirar hipolipemiantes, hipolipemiantes por lovastatina en prevención primaria, antiinflamatorios no esteroideos (AINE) nuevos por AINE clásicos y uso de Especialidades Farmacéuticas Genéricas (EFG). b) Intervenciones que utilizar. Se encontraron 5 intervenciones en las que la evidencia sugería su utilización: entrevistas cara a cara, información de retorno, incentivos económicos, presupuestación individual y sesiones y visitas al EAP. c) Resistencias esperables, Se identificaron varios resistencias: vivencia de las entrevistas cara a cara como llamadas de atención, resistencia a cambio a medicamentos de menor coste y no mayor utilidad, así como la prescripción inducida por atención especializada

This paper describes the activities performed in control o f drug cost in a Health Core Area (Area 2 of Madrid). It establishes three work lines: a) define what group o f medications to act on based on their financial impact, b) define what interventions to use on based on the existing evidence and apply them and c) initiate a management process o f change, detecting resistances and diffculties. For the first line, alternative are established, based on evidence, for the drugs prescribed most and the port o f the cost that would have been avoided in case o f applying the alternative is determined. It was necessary to perform usage studies in several drug groups. In the second work line, a bibliographic review was performed and a critical assessment o f the evidence found. For the third line, a group o f representatives o f each primary health core team (PHCT) was formed and interviews were given to the clinical leaders o f the PHCTs. Results. a) Drugs on which to act. The following changes were chosen (all refer to those situations in which the change is indicated):ACEls and calcium antagonists to diuretics, ARA II to ACEls, Withdraw lipid lowering drugs, Lipid lowering drugs to lovastatin in primary prevention, new NSAIDs to classical NSAIDs, GMP b) Interventions to be used. Five interventions in which the evidence suggested their use were found head to head interviews, feedback, financial incentives, individual budgeting and sessions and visits to the PCHT c) Expectable resistances. Several resistances were identified experience o f the head to head interviews as calls o f attention, resistance to change to drugs having lower cost and not greater utility and specialized cure induced prescription

¿Contratar más suplentes puede ser una herramienta para mejorar la racionalidad de la prescripción? / Can taking on more locums be a tool to make prescription more rational?

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