Project Description Narrative:
The American Cancer Society estimates that one in eight women will develop breast cancer in her lifetime. Breast cancer is the second most common cancer in women in the United States, accounting for approximately 30% of all new female cancers each year. In 2023, about 297,790 new cases of invasive breast cancer will be diagnosed in U.S. women, and 43,700 will die from this disease. In Wisconsin, the incidence of breast cancer in women is on the rise. From 2015 to 2019, the average annual incidence rate of female breast cancer was 135/100,000, topping all other cancer types and surpassing the national average of 127/100.000. Advancements in therapeutic regimens provide improved control of the systemic disease and prolong survival. However, this is associated with an increased likelihood of developing brain metastases.
The risk of brain metastasis is usually highest for people with more aggressive subtypes of breast cancer, such as human epidermal growth factor receptor 2 (HER2)-positive or hormone and HER2 receptor-negative (triple-negative) breast cancer. At diagnosis, 5–10% of breast cancer patients are found to have metastatic disease, and a similar proportion is deemed inoperative. Yet, the true incidence of brain metastases in patients with breast cancer may be underestimated. At autopsy, brain metastases are found in up to 30% of patients with breast cancer. Patients with metastatic disease will undergo chemotherapy in addition to surgery and radiation therapy. Unfortunately, almost 35% of those patients do not respond and usually fewer than 30% obtain a complete or optimal response. Limitations that diminish chemotherapy efficacy include problems related to low solubility, inefficient tumor targeting, significant toxicities in healthy tissues (most notably in the heart and brain), and the development of drug resistance.
Moreover, low efficacy of systemic chemotherapeutics in brain metastases of breast cancer is thought to be largely due to the poor penetration of these agents through the blood–brain barrier. Thus, there is an urgent need to develop novel therapies for the treatment of breast cancer brain metastases. Iron plays a vital role in the pathobiology of many cancers, including breast 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 breast 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. Gallium 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 will test the cytotoxic potential of a novel iron mimetic metallocompound, GaM, in a panel of patient-derived cell lines with metastatic potential. Additionally, the researchers seek to submit patient specimens of primary breast cancer and brain metastases for immunohistochemistry (IHC) to identify specific iron-related protein profiles that may serve as biomarkers predictive of which patient populations will benefit the most from iron-targeted therapy with GaM.