Disease X: accelerating the development of medical countermeasures for the next pandemic.

WHO has listed several priority diseases with epidemic potential for which there are no, or insufficient, medical countermeasures. In response, the Bill & Melinda Gates Foundation (with support from PricewaterhouseCoopers) coordinated subject matter experts to create a preparedness plan for Disease X. Disease X is caused by Pathogen X, an infectious agent that is not currently known to cause human disease, but an aetiologic agent of a future outbreak with epidemic or pandemic potential. We have identified crucial areas for acceleration in medical countermeasure product development and international coordination. We have also reviewed novel platforms and process improvements related to manufacturing, which could revolutionise the response to the next pandemic. Finally, we created several coordination and engagement guides. These guides range from the rational design of an intervention target product profile, to the key facets of vaccine and therapeutic development, to accelerated manufacturing and regulatory mechanisms. In this Personal View, we provide a high-level summary of the outcomes of the medical countermeasure development workstream, intended for a broad audience including academia, medical countermeasure developers, and multilateral coordinating bodies. We hope that they might find this piece useful in prioritising strategic investments and efforts to accelerate medical countermeasure development. We observed that in-depth analyses of clinical trial design, chemistry, manufacturing and control activities, and accelerated regulatory pathways are necessary for shortening the timelines for the product development of medical countermeasures. We intend to cover these topics in future publications.

Combined inhibition of MAP kinase and KIT signaling synergistically destabilizes ETV1 and suppresses GIST tumor growth.

UNLABELLED: Gastrointestinal stromal tumor (GIST), originating from the interstitial cells of Cajal (ICC), is characterized by frequent activating mutations of the KIT receptor tyrosine kinase. Despite the clinical success of imatinib, which targets KIT, most patients with advanced GIST develop resistance and eventually die of the disease. The ETS family transcription factor ETV1 is a master regulator of the ICC lineage. Using mouse models of Kit activation and Etv1 ablation, we demonstrate that ETV1 is required for GIST initiation and proliferation in vivo, validating it as a therapeutic target. We further uncover a positive feedback circuit where MAP kinase activation downstream of KIT stabilizes the ETV1 protein, and ETV1 positively regulates KIT expression. Combined targeting of ETV1 stability by imatinib and MEK162 resulted in increased growth suppression in vitro and complete tumor regression in vivo. The combination strategy to target ETV1 may provide an effective therapeutic strategy in GIST clinical management. SIGNIFICANCE: ETV1 is a lineage-specific oncogenic transcription factor required for the growth and survival of GIST. We describe a novel strategy of targeting ETV1 protein stability by the combination of MEK and KIT inhibitors that synergistically suppress tumor growth. This strategy has the potential to change first-line therapy in GIST clinical management.