Abstract

Targeting Cancer-Stromal Cell Communication by Novel Drugs that Disrupt the Nuclear Entry of Extracellular Vesicles

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

Extracellular vesicles (EVs) are mediators of intercellular communication under both healthy and pathological conditions, including the induction of pro-metastatic traits, but it is not yet known how and in which host cell compartment(s) EVs deliver their functional cargo. We recently described a novel intracellular pathway whereby EV-containing late endosomes enter in the nucleoplasmic reticulum through type II nuclear envelope invaginations (NEI) and transfer EV cargo into the nucleoplasm of recipient cells. A tripartite protein complex named VOR, containing nuclear membrane-associated VAP-A, ORP3 and late endosome-associated Rab7 orchestrates entry and/or docking of EV-containing late endosomes into NEI. In search for drugs that could inhibit ORP3 function as component of the VOR complex, we came across ORPphilin molecules, such as anti-proliferative natural product OSW-1 and the FDA-approved antifungal azole itraconazole (ICZ). In addition to its antifungal activity, due to the inhibition of lanosterol 14a-demethylase, an inhibitory activity of ICZ on enterovirus and hepatitis C virus replication has been reported and attributed to OSBP and ORP4 inhibition. The five ring-backbone structure and the sec-butyl chain of ICZ are important for antiviral activity, whereas the triazole moiety is critical for the antifungal activity. We recently found that ICZ, but not its main metabolite hydroxy-ICZ or ketoconazole, disrupts the VOR complex and inhibits EV-mediated pro-metastatic morphological transformation and migratory properties of colon cancer cells. By computer modelling, we have synthesized novel, smaller chemical drugs, that maintain the property of inhibiting the VOR complex without the ICZ moieties responsible for the antifungal activity and interference with intracellular cholesterol distribution. Knowing that cancer cells hijack their microenvironment and that EVs derived from them determine the pre-metastatic niche, small-sized inhibitors of nuclear transfer of EV cargo into host cells could find cancer therapeutic applications, particularly in combination with direct targeting of cancer cells.