Metabolism-Targeted Strategies for Cancer Chemoprevention

Two metabolism-based strategies aimed at female reproductive cancers, including ovarian cancers and uterine cancers, will be covered in this seminar. (1) Glutamine is an important α-amino acid that provides carbon and nitrogen sources for the biosynthesis of nucleotides, proteins, and lipids. Malignant cells have a heightened metabolic dependence on glutamine to support incessant tumor growth and mitigate tumor microenvironmental stresses including hypoxia, nutrient depletion, and oxidative stress. Targeting tumor metabolism can starve cancer cells and elicit anti-tumor effects. However, most anti-cancer metabolism drugs suffer from its toxicity to healthy tissues, thus limiting its clinical use. We have developed a prodrug approach by conjugating a glutamine antagonist DON to an isopropyl ester and acetylated tryptophan moieties. In tissues such as tumors with overexpressed proteases and esterases, the ester and peptide bonds are cleaved, releasing the active DON directly within the tumor tissues. Notably, this prodrug strategy is highly potent in syngeneic mouse models with intact immune systems, but markedly less effective in vitro or in immunodeficient mice. Findings from our lab indicated that the prodrug exerted its anti-tumor efficacy through not only direct targeting glutamine-addicted cancer cells but also by suppressing glutamine-dependent M2 macrophages, leading to a shift in the M1/M2 macrophage landscape in favor of an immune-stimulatory microenvironment. The findings suggest that, in addition to targeting cancer cells directly, regulating immune cell metabolism may provide new avenues for the development of metabolism-based therapies for the treatment of cancer. (2) Another direction we pursue is identifying safer, tolerable anti-tumor regimens by repurposing FDA-approved drugs used for other medical indications. Through analyses of ovarian cancer clinical data from the US Collaborative Network, we confirmed that statin users have better clinical outcomes than non-statin users. We next investigated the protective effects in murine model(s) of ovarian cancer and identified increased M1-like macrophages and activated CD8+ T-cell populations, indicating statin use may reshape tumor immune microenvironment and enhance overall T-cell immunity. Such benefits of statin use may extend beyond ovarian cancer patients, as studies have shown that prolonged statin use is linked to reduced cancer-associated mortality across multiple cancer types.

Speaker: Prof. Tian-Li Wang (Professor, Departments of Pathology, Oncology, and Gynecology/Obstetrics Director, Laboratory of Molecular Genetics of Female Reproductive Cancers Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, USA)

Host: Dr. Yu-Ling Lin

Time:2026/11/02 11:00 AM

Location:Auditorium A134, Agricultural Technology Building