Project Description Narrative:
An estimated 24,810 new cases of brain cancer will be diagnosed in 2023, with an estimated 18,990 deaths. In Wisconsin, both the incidence (7) and death rates (4.8) per 100,000 surpass the national ones of 6.4 and 4.4, respectively. Glioblastoma (GBM) is an extremely aggressive cancer for which there are limited treatment options. Despite recent advances in therapy, the prognosis remains dismal and patient survival is short.
After standard therapy, which includes surgical resection followed by chemotherapy and radiation, the residual or recurrent tumor frequently becomes resistant to therapy, rendering it an extremely difficult disease to treat. One factor responsible for the poor response to treatment is the increase in heterogeneity of tumor cell populations comprising predominantly treatment-resistant GBM (trGBM) cells with cancer stem cell characteristics. This shift in genomic makeup of trGBM results in a decidedly aggressive tumor phenotype with no known cure. Cancer iron metabolism is an attractive target for therapeutical intervention. Iron plays a vital role in the pathobiology of many cancers, including brain cancer, where it drives several iron-dependent processes involved in upregulated DNA repair, drug resistance, and enhanced malignant cell proliferation. The role of iron in brain cancer biology is well established. Iron binds to its transport protein transferrin (Tf) and is taken up by cancer cells via transferrin receptors (TfRs) that populate the cell surface. This mode of transport can be hijacked by gallium. This heavy metal is known to interfere with iron metabolism by acting as an iron mimetic, since it shares several chemical properties with iron. However, unlike iron, gallium cannot take part in cellular redox reactions. Consequently, cancer cells take up gallium like they would iron, but once within the cell, gallium disrupts critical iron-dependent processes resulting in cell death.
This project’s research team has demonstrated the effectiveness of gallium maltolate (GaM), a newer generation compound with high oral bioavailability and therapeutic index, both in vitro and in vivo. Based on their promising preclinical in vivo results, a Phase I clinical trial was launched at MCW. However, pressing questions remain regarding response to therapy. To plan future studies and inform a Phase II clinical trial, the team will elucidate whether sensitivity to GaM is predetermined by pre-treatment iron protein expression and GaM alters iron metabolism in trGBM such that it may affect sensitivity to iron-targeted therapy. More specifically, they seek to understand the differential protein expression profiles of short-term survivors vs. long-term survivors and what determines complete resolution.