Aurelio Lorico,
Professor of Pathology,
Touro University Nevada School of Medicine
Aurelio Lorico did his post-doc at Yale University, mentored in the pharmacology field by Alan Sartorelli. Later, as Junior Research Faculty at Yale he clarified the biological function(s) of the MRP1 gene by generating and characterizing MRP1 knockout mice and cell lines. After 8 years at Yale, he became senior scientist at the Norwegian Cancer Center in Oslo, working on cancer drug resistance and designing new strategies for gene therapy of hereditary diseases. Back to the US, he has been working on cell-to-cell communication in the tumor microenvironment, particularly cell-cell fusion and extracellular vesicles, and on the development of innovative therapeutic strategies for breast cancer, melanoma and glioblastoma. His lab has recently discovered the mechanism of nuclear transport of the cargo of extracellular vesicles and has synthesized new drugs that block the transport and have anti-cancer metastatic activity.
Targeting Cancer-Stromal Cell Communication by Novel Drugs that Disrupt the Nuclear Entry of Extracellular Vesicles
Wednesday, 15 December 2021 at 11:30
Add to Calendar ▼2021-12-15 11:30:002021-12-15 12:30:00Europe/LondonTargeting Cancer-Stromal Cell Communication by Novel Drugs that Disrupt the Nuclear Entry of Extracellular VesiclesExtracellular Vesicles (EVs): Technologies and Biological Investigations in Coronado Island, CaliforniaCoronado Island, CaliforniaSELECTBIOenquiries@selectbiosciences.com
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.
Add to Calendar ▼2021-12-13 00:00:002021-12-15 00:00:00Europe/LondonExtracellular Vesicles (EVs): Technologies and Biological InvestigationsExtracellular Vesicles (EVs): Technologies and Biological Investigations in Coronado Island, CaliforniaCoronado Island, CaliforniaSELECTBIOenquiries@selectbiosciences.com
Add to Calendar ▼2021-12-15 11:30:002021-12-15 12:30:00Europe/LondonTargeting Cancer-Stromal Cell Communication by Novel Drugs that Disrupt the Nuclear Entry of Extracellular VesiclesExtracellular Vesicles (EVs): Technologies and Biological Investigations in Coronado Island, CaliforniaCoronado Island, CaliforniaSELECTBIOenquiries@selectbiosciences.com
