Friday, April 4, 2025
4/4/2025
Exploiting oxidative stress response in uveal melanoma liver metastases - ABSTRACT: Uveal melanoma (UM) is the most aggressive form of intraocular cancer in adults. Primary disease can be effectively treated however, ~50% of patients will develop metastasis. Unfortunately, metastatic lesions are often fatal within one year of diagnosis; making UM one of the most lethal cancers. Metastatic UM has strong liver tropism and are refractory to standard treatments. As there is a clear unmet clinical need for viable treatment options, the overarching goal of this application is to highlight novel therapeutic avenues to treat metastatic UM. Since most UM metastases are found in the liver and are responsible for poor prognosis, we seek to better understand how the liver microenvironment supports metastatic UM. In this proposal, we will use in vitro, ex vivo organotypic liver slice co-culturing, and in vivo experimental modalities to investigate: 1.) How UM liver metastases are susceptible to ferroptosis – a programed cell death pathway associated with the accumulation of toxic lipid peroxides. Publicly available datasets and our preliminary data demonstrate that loss of BAP1 – a strong determinant of liver metastases, is associated with ferroptotic resistance. Furthermore, we found that mutant BAP1 UM can better cope with stresses imposed by a lipid-rich microenvironment. Lastly, our preliminary data suggest mutant BAP1 UM are more sensitive to pharmacological inhibition of anti-ferroptotic machinery than wildtype BAP1 counterparts. 2.) Investigate how liver associated selenoproteome expression help UM stave off oxidative stress. The liver is the body’s selenium repository and many genes associated with ameliorating ferroptotic or oxidative stress are selenoproteins – proteins that have at least once selenium containing amino acid, selenocysteine. Preliminary in vitro and ex vivo liver slice experimentation demonstrate enhanced selenoproteome expression when UM cells are dosed with exogenous selenium compounds or liver conditioned media. These data are supported by transcriptomic expression patterns that indicate BAP1 loss (likely metastatic) is associated with increased genes that facilitate selenoprotein synthesis. 3.) Determine how targeting ferroptosis and the selenoproteome in UM liver metastases modulates the tumor immune microenvironment. Since ferroptosis is an immunogenic cell death pathway, we will use syngeneic systems to highlight how ferroptosis or reduced selenoproteome expression activate both innate and peripheral anti-UM immune responses. Specifically we will investigate how these stresses stimulate the phagocytic activity of hepatic macrophage-like cells including Kupffer cells. Moreover, we will use syngeneic in vivo modeling to test how pharmacological induction of ferroptosis or genetic based reduction of selenoproteome expression shapes the hepatic tumor immune microenvironment. By investigating the points highlighted above, we will gain mechanistic insights and highlight therapeutic vulnerabilities associated with the unique interplay between the liver microenvironment and UM metastases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).