The role of CRAF in cancer progression: from molecular mechanisms to precision therapies.

The RAF family of kinases includes key activators of the pro-tumourigenic mitogen-activated protein kinase pathway. Hyperactivation of RAF proteins, particularly BRAF and CRAF, drives tumour progression and drug resistance in many types of cancer. Although BRAF is the most studied RAF protein, partially owing to its high mutation incidence in melanoma, the role of CRAF in tumourigenesis and drug resistance is becoming increasingly clinically relevant. Here, we summarize the main known regulatory mechanisms and gene alterations that contribute to CRAF activity, highlighting the different oncogenic roles of CRAF, and categorize RAF1 (CRAF) mutations according to the effect on kinase activity. Additionally, we emphasize the effect that CRAF alterations may have on drug resistance and how precision therapies could effectively target CRAF-dependent tumours. Here, we discuss preclinical and clinical findings that may lead to improved treatments for all types of oncogenic RAF1 alterations in cancer.

Pharmacology active microcarriers delivering HGF associated with extracellular vesicles for myocardial repair.

Despite the curative approaches developed against myocardial infarction, cardiac cell death causes dysfunctional heart contractions that depend on the extent of the ischemic area and the reperfusion period. Cardiac regeneration may allow neovascularization and limit the ventricular remodeling caused by the scar tissue. We have previously found that large extracellular vesicles, carrying Sonic Hedgehog (lEVs), displayed proangiogenic and antioxidant properties, and decreased myocardial infarction size when administrated by intravenous injection. We propose to associate lEVs with pharmacology active microcarriers (PAMs) to obtain a combined cardioprotective and regenerative action when administrated by intracardiac injection. PAMs made of poly-D,L-lactic-coglycolic acid-poloxamer 188-poly-D,L-lactic-coglycolic acid and covered by fibronectin/poly-D-lysine provided a biodegradable and biocompatible 3D biomimetic support for the lEVs. When compared with lEVs alone, lEVs-PAMs constructs possessed an enhanced in vitro pro-angiogenic ability. PAMs were designed to continuously release encapsulated hepatocyte growth factor (PAMsHGF) and thus, locally increase the activity of the lEVs by the combined anti-fibrotic properties and regenerative properties. Intracardiac administration of either lEVs alone or lEVs-PAMsHGF improved cardiac function in a similar manner, in a rat model of ischemia-reperfusion. Moreover, lEVs alone or the IEVs-PAMsHGF induced arteriogenesis, but only the latter reduced tissue fibrosis. Taken together, these results highlight a promising approach for lEVs-PAMsHGF in regenerative medicine for myocardial infarction.

Scaffolds and Extracellular Vesicles as a Promising Approach for Cardiac Regeneration after Myocardial Infarction.

Clinical studies have demonstrated the regenerative potential of stem cells for cardiac repair over the past decades, but their widespread use is limited by the poor tissue integration and survival obtained. Natural or synthetic hydrogels or microcarriers, used as cell carriers, contribute to resolving, in part, the problems encountered by providing mechanical support for the cells allowing cell retention, survival and tissue integration. Moreover, hydrogels alone also possess mechanical protective properties for the ischemic heart. The combined effect of growth factors with cells and an appropriate scaffold allow a therapeutic effect on myocardial repair. Despite this, the effects obtained with cell therapy remain limited and seem to be equivalent to the effects obtained with extracellular vesicles, key actors in intercellular communication. Extracellular vesicles have cardioprotective effects which, when combined proangiogenic properties with antiapoptotic and anti-inflammatory actions, make it possible to act on all the damages caused by ischemia. The evolution of biomaterial engineering allows us to envisage their association with new major players in cardiac therapy, extracellular vesicles, in order to limit undesirable effects and to envisage a transfer to the clinic. This new therapeutic approach could be associated with the release of growth factors to potentialized the beneficial effect obtained.