Breast cancer is the most common malignancy in women. Young African American (AA) women are affected by a higher incidence and mortality rate of triple-negative breast cancer (TNBC) compared to Non-Hispanic White (NHW) women. Currently, available treatment options are suboptimal, with a 5-year survival of less than 12% for metastatic TNBC. Our laboratory demonstrated that IGF-2 plays a pivotal role in the tumor aggressiveness of AA women. Moreover, tissues from AA women express high levels of IGF-2 and exhibit high activation of IGF-2 signaling pathways associated with tumorgenesis and chemoresistance. An emerging pathway linked to IGF-2 mediated chemoresistance and cell survival in TNBC is the regulation of mitochondrial and survival proteins. Mitochondrial Magmas is a mitochondrial protein found in all eukaryotic cells that is required for cell viability. It functions to transport nuclear proteins from the inner mitochondrial membrane to the mitochondrial matrix. Magmas can buffer increased reactive oxidative species (ROS) and promote survival of cancer cells. Overexpression of Magmas reduced ROS and enhanced cellular tolerance to oxidative stress; however, its downregulation raised cellular ROS and made cells more vulnerable to ROS-mediated death. Given the role of IGF-2 in regulating mitochondrial proteins, we investigated if IGF-2 regulated Magmas. We hypothesize that IGF-2 increases Magmas, and since AA women express higher levels of IGF-2, they will express higher Magmas levels. We used the CRL-2335 AA TNBC cell line and an IGF-2 knockdown of those same cells. Western blotting was used to detect the specific isoforms of IGF-2 and Magmas from cell lysates. Immunohistochemistry (IHC) characterized Magmas expression in paired, normal-tumor breast cancer tissues. Real time PCR was used to evaluate the expression of IGF2 and MAGMAS. The preliminary results showed that IGF-2 knockdown in CRL-2335 AA TNBC cells significantly decreased Magmas protein expression and its corresponding mRNA. In addition, tissue analysis demonstrated high levels of Magmas staining in TNBC tissue while little or no staining was detected in the normal tissues. Furthermore, tumor tissues of AA women showed significantly higher expression of Magmas as compared to tissues from NHW women. Targeting Magmas represents a novel and much needed tool to treat TNBC. Our team is currently validating Magmas as a target for Theranostics treatment, a promising emerging radiotherapy for TNBC patients. Citation Format: Jennifer D. Tran, Alfonso D. Duran, Qian-Wei Tan, Frankis G. Almaguel, Daisy De León. IGF-II regulates a critical mitochondrial protein, Magmas, with differential expression between African American and Non-Hispanic White women with TNBC [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C064.

Metastatic prostate cancer (PCa) is the leading cause of PCa-associated deaths and one of the leading causes of cancer mortality in men. Novel therapeutics, such as Prostate Specific Membrane Antigen (PSMA) ligand therapy, are emerging as effective treatment strategies for metastatic prostate cancer. However, neuroendocrine differentiated (NED) metastatic PCa, which lacks the PSMA antigen, is deprived of effective biomarkers for disease treatment. Magmas, a 13.8 kDa mitochondrial protein, imports nuclear-encoded mitochondrial proteins into the mitochondrial matrix. Magmas is overexpressed in several aggressive tumors, such as breast cancer, glioblastoma, and prostate cancer. When overexpressed, Magmas plays a role as a cytoprotective protein by acting as a reactive oxygen species (ROS) scavenger that maintains sufficient ROS levels to promote cell proliferation, but below the threshold levels that could lead to apoptosis. This study was designed to investigate the pro-survival and therapy-resistance functions of Magmas in PCa cells expressing NED markers. Predictively, we observed that the docetaxel (DTX)-resistant PC3-DR and DU145-DR PCa cell lines expressed significantly higher levels of Magmas compared to their drug-sensitive parental cell lines. We hypothesized that inhibiting Magmas reduces the aggressive properties of highly proliferative DTX- resistant metastatic PCa cell lines and re-sensitize them to DTX. Magmas knockdown in DTX-sensitive and DTX-resistant PC3 and DU145 cells in the presence of increasing DTX treatments enhanced sensitivity to DTX. Consistent with these results, pharmacological inhibition of Magmas with the novel BT#9 inhibitor in combination with increasing DTX concentrations also enhanced sensitivity to DTX in these cell lines. Additional studies using clonogenic assays, cell migration/invasion assays, and tumorsphere formation assays are currently underway to further establish Magmas as a potential therapeutic target to attenuate the aggressive properties of chemoresistant PCa cells. Lastly, we will investigate the diagnostic potential of Magmas as a biomarker for NED and BT#9 as an imaging/therapeutic-specific agent for NED. Citation Format: Alfonso M. Durán, Christian H. Yoo, Jennifer D. Tran, Krystal Santiago, Adil S. Mohammed, Carlos A. Casiano, Frankis A. Almaguel. Targeting the mitochondrial protein MAGMAS increases sensitivity to docetaxel in neuroendocrine prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1754.