Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma

Neuroblastoma is the most common paediatric solid tumour and prognosis remains poor for high-risk cases despite the use of multimodal treatment. Analysis of public drug sensitivity data showed neuroblastoma lines to be sensitive to indisulam, a molecular glue that selectively targets RNA splicing factor RBM39 for proteosomal degradation via DCAF15-E3-ubiquitin ligase. In neuroblastoma models, indisulam induces rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15-dependent manner. Integrative analysis of RNAseq and proteomics data highlight a distinct disruption to cell cycle and metabolism. Metabolic profiling demonstrates metabolome perturbations and mitochondrial dysfunction resulting from indisulam. Complete tumour regression without relapse was observed in both xenograft and the Th-MYCN transgenic model of neuroblastoma after indisulam treatment, with RBM39 loss, RNA splicing and metabolic changes confirmed in vivo. Our data show that dual-targeting of metabolism and RNA splicing with anticancer indisulam is a promising therapeutic approach for high-risk neuroblastoma

Corporate governance for sustainability : Statement

The current model of corporate governance needs reform. There is mounting evidence that the practices of shareholder primacy drive company directors and executives to adopt the same short time horizon as financial markets. Pressure to meet the demands of the financial markets drives stock buybacks, excessive dividends and a failure to invest in productive capabilities. The result is a ‘tragedy of the horizon’, with corporations and their shareholders failing to consider environmental, social or even their own, long-term, economic sustainability. With less than a decade left to address the threat of climate change, and with consensus emerging that businesses need to be held accountable for their contribution, it is time to act and reform corporate governance in the EU. The statement puts forward specific recommendations to clarify the obligations of company boards and directors and make corporate governance practice significantly more sustainable and focused on the long term

The role of biophysics and engineering in investigating tumour pH and its regulation

Solid tumours tend to have a high metabolic rate, inducing the intracellular accumulation of lactic acid and CO2 with a concomitant decrease in pH. Since many intracellular processes are pH-sensitive, tumour progression is therefore dependent on the maintenance of intracellular and extracellular pH within a narrow range. Cancer cells employ a number of functionally redundant regulatory mechanisms to maintain pH homeostasis. Several small molecule inhibitors which target these mechanisms are currently in clinical trials with promising outcomes. In order to investigate tumour pH regulation and to stratify and monitor patient response to these treatments, we need to be able to accurately measure pH in situ. Although pH measurement techniques are continually being developed, they are still limited for example by poor probe targeting and spatio-temporal resolution. In this review, we discuss the important role of biophysics and engineering in tackling the challenges faced when measuring tumour pH