Abstract

Anti-Metastatic Activity of PRR851, A Specific Inhibitor of the Nuclear Transport of Extracellular Vesicles

Aurelio Lorico, Professor of Pathology, Touro University Nevada School of Medicine

The metastatic process is responsible for the vast majority of cancer deaths, yet most therapeutic efforts have focused on targeting and interrupting tumor growth rather than impairing metastasis. Identifying and testing new pathways to disrupt the process of metastasis is the key to developing new therapeutic strategies that improve cancer survival. We have identified and described a novel cellular pathway that allows extracellular vesicles (EVs) derived from cancer cells to transfer oncogenic cargoes into the nuclear compartment of mesenchymal stromal cells and transform their gene expression. This pathway relies on the translocation of Rab7+ late endosomes, which contain endocytosed EVs, into the nucleoplasmic reticulum (NR) of recipient stromal cells. The interaction between the two organelles; late endosomes and the nucleus, is mediated by a novel tripartite protein complex (named VOR) formed by VAMP-associated protein A (VAP-A) in the outer nuclear membrane, cytoplasmic oxysterol-binding protein -related protein-3 (ORP3) and endosomal Rab7 GTPase. Silencing VAP-A or ORP3 in recipient cells prevents late endosome entry into the NR, thereby blocking EV-mediated intercellular communication. We have designed and synthesized new chemical entities (NCEs) that inhibit VOR complex formation and nuclear transfer of EV cargoes. We have identified a lead NCE (PRR851), that reduced the incidence of metastasis in a syngeneic mouse model of malignant melanoma without apparent off-target toxicity. We will discuss the structure-activity relationship of PRR851 and its analogs and new data in experimental metastasis systems.