Abstract A060: Lactotransferrin drives glioblastoma progression via apoptosis suppression in an iron-independent manner

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor, known to be highly aggressive with a median survival of only ∼15 months. The prognosis of glioblastoma (GBM) patients have not significantly improved over the last few decades, with current treatment strategies failing largely due to the tumor’s ability to resist regulated cell death processes. This factor not only drives tumor progression but also results in therapeutic resistance as the current standard of care approaches such as radiation and chemotherapy kills the cancer cells by inducing cell death (primarily apoptosis). Lactotransferrin (LTF) is an iron-binding glycoprotein with multi-dimensional biological properties. Recent studies have reported that LTF influences tumor cell proliferation, sensitivity towards irradiation and TMZ treatment, and patient survival in various cancer types. However, the role of LTF in GBM still remains unclear. Our preliminary data from the analysis of human GBM samples revealed that LTF is upregulated in tumors when compared to non-tumor conditions, and elevated levels of LTF in GBM tumor cells drives cell growth and proliferation, resulting in a reduction in survival in the context of in vivo syngeneic GBM models. Furthermore, genetically knocking down LTF reduced GBM cell growth and proliferation while resulting in an extension in survival with in vivo syngeneic GBM models. Mechanistically, we observed that reduced LTF levels in GBM tumor cells induced iron-independent apoptotic cell death and further limits tumor growth through inactivation of the AKT singaling pathway to limit tumor progression. Further, synergistic effect of LTF inhibition and irradiation on GBM tumor cells reduces reduces tumor cell growth in vitro.Ongoing studies are evaluating strategies to improve survival in syngeneic GBM murine models by depleting LTF levels to suppress GBM growth, while increasing sensitivity to the current standard of care therapies, radiation and chemotherapy. These preclinical findings demonstrate that LTF is essential for GBM cell survival and provide support that LTF modulation in GBM may open opportunities for novel treatment approaches with improved efficacy. Citation Format: Swapnil Dey, Anthony R. Sloan, Daniel Silver, Erin Mulkearns, Cole Smith, Justin D. Lathia, Matthew M. Grabowski. Lactotransferrin drives glioblastoma progression via apoptosis suppression in an iron-independent manner [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A060.