Saturday, May 31, 2025
5/31/2025
Investigating the role of sulfide oxidation and declining hydrogen sulfide in glioblastoma - PROJECT SUMMARY Glioblastoma (GBM) is a malignant brain tumor responsible for significant morbidity and mortality. Despite efforts to develop new and more efficacious therapeutic options for GBM, long-term survival rates trail other cancers, and a diagnosis remains universally lethal. Poor outcomes are the result of many factors, including invasion into healthy tissue beyond the reach of conventional therapies such as surgery or radiation, cellular heterogeneity which causes many chemotherapeutic agents to fail, and a highly immunosuppressive environment limiting the effectiveness of immunotherapy. The inability to improve patient survival is greatly influenced by intrinsic factors that enable cells to evade death and adapt to a new or changing environment. However, consideration of patient age as a risk factor provides the greatest predictive value for response to therapy, and disease progression. While GBM does occur in younger individuals, incidence rates increase with age, and most diagnoses occur in patients over 65 years. Aging also negatively influences length of survival. Therefore, understanding factors that contribute to this relationship will improve patient care for the majority of glioblastoma patients. One factor associated with healthy aging, increased lifespan, and reduced incidence of aging-associated morbidities is a gas known as hydrogen sulfide (H2S). This sulfur containing gas, recognizable by its rotten egg smell, provides multiple health benefits at low and supraphysiological levels, but is toxic at extremely high doses. The proposed studies in this F31 fellowship application focus on the role of H2S in suppressing tumor growth in glioblastoma and promoting anti-tumor immunity, as well as understanding what role aging has on H2S removal mediated by sulfide oxidation. Preliminary data indicates that sulfide oxidation is increased in GBM relative to non-malignant brain tissue and lower grade gliomas. A pattern reflected by decreased survival. Additionally, inhibition of sulfide oxidation results in decreased proliferation of GBM cells in vitro, likely mediated by the observed decrease in H2S. Based upon these observations, I hypothesize that sulfide oxidation increases in older individuals, thus driving the aging-related decline in H2S that enables tumor growth while also promoting an immunosuppressive tumor microenvironment. I plan to test this hypothesis using two experimental aims. Aim 1 will test the hypothesis that age-dependent upregulation of sulfide oxidation in GBM leads to reduced H2S signaling and accelerated disease progression, while simultaneously stimulating mitochondrial electron transport. Aim 2 will test the hypothesis that declining H2S signaling in aging contributes to immunosuppressive nature of GBM. These aims will be accomplished using in vitro and in vivo systems for manipulating expression of sulfide oxidizing enzymes and H2S levels, based upon pharmacological, genetic, and aging approaches. If successful, this project will elucidate the role of sulfide oxidation in GBM. A previously unexplored pathway that may identify new therapeutic targets for treating and managing glioblastoma in combination with current standard of care treatments.
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).