The year 2021 marks a grim milestone for breast cancer seeing it overtake lung cancer to become the most commonly diagnosed cancer globally. Around one in eight U.S. women is expected to develop breast cancer over the course of her lifetime, and nearly one in 40 will die from it. These figures have renewed urgency within the scientific community to come up with better strategies for treating this disease, including researchers at Rutgers Cancer Institute of New Jersey and Rutgers New Jersey Medical School (NJMS). In a new study, they discovered a phage display-based approach to halt tumor growth that could be used to treat triple-negative breast cancer – considered the most aggressive type of breast cancer. The findings were published online in the scientific journal eLife (DOI: https://doi.org/10.7554/eLife.65145). In triple-negative breast cancer (TNBC), cancer cells lack three proteins that are seen in most other breast cancer types. Although TNBC only makes up around 15% of all breast cancer cases, it causes most of the deaths. This is because current treatments, which are generally combination chemotherapy regimens, are not usually sufficient to control it. For cancer to survive in the body, it somehow needs to bypass all the control checkpoints and mechanisms that exist to keep the human body healthy. One of these mechanisms is our immune system, which seeks out and destroys foreign cells such as bacteria and viruses, as well as abnormal cancer cells. As TNBC grows, it recruits immune cells called macrophages that uniquely associate with the tumor and essentially protect it from being destroyed by the immune system. Rutgers investigators hypothesized that these immune cells, tumor-associated macrophages (TAM), could be exploited as the tumor’s Achilles’ heel. Their study shows how this can be accomplished by using a distinct molecule on the surface of the TAM and another one that can target it. They discovered these two molecules by using a technology known as in vivo phage display, which can be used like a fishing line to pull out of a large sea of small molecules the one or two that specifically bind to the surface of TAM. One of the molecules they fished out targeted a vitamin D-binding receptor called protein disulfide-isomerase A3 (PDIA3) on the cell surface of TAM. They found that PDIA3 also marked TAM in breast cancer patients who had poor prognosis, like TNBC. The team used mouse models to grow human breast tumors so they could mimic a patient scenario as closely as possible. They found that the TAM-binding ligand peptide that they fished out with their phage display method targets the vitamin D receptors on the cell surface of non-malignant TAM and can kill it by removing its tumor-protective effects, thus halting tumor growth. The lead author of the study is Fernanda I. Staquicini, PhD, who conducted the work while a resident member of Rutgers Cancer Institute, and assistant professor of radiation oncology in the Division of Cancer Biology, Department of Radiation Oncology at Rutgers NJMS, who is the current director of Research & Development at MBrace Therapeutics in Summit, New Jersey. Dr. Staquicini notes, “This exciting work uncovers a potential functional role of immune cells in combating triple-negative breast cancer; if confirmed in future studies, targeted development of an immune-subversion mechanism-based drug lead against this devastating disease might well be within reach.” “What differentiates this strategy from most of the approaches used to treat breast cancer is we are targeting the non-malignant cellular guards of the tumor (TAM), and not the cancer cells themselves. Upon ligand-receptor binding, TAM goes from being a breast cancer promoter to being a breast cancer suppressor, which is an entirely novel mechanism of action. This study provides a much-needed glimpse of hope in targeted drug discovery and development against triple-negative breast cancer,” shares the study’s senior author Renata Pasqualini, PhD, resident member of Rutgers Cancer Institute and professor and founding chief of the Division of Cancer Biology, Department of Radiation Oncology at Rutgers NJMS. Her mother’s fight against TNBC is what inspired her academic career as a cancer biologist. The study’s other senior author, Wadih Arap, MD, PhD, director of Rutgers Cancer Institute at University Hospital Newark and professor and chief of the Division of Hematology/Oncology, Department of Medicine, Rutgers NJMS, sums up the study: “Human triple-negative breast cancer is one of the ultimate unmet needs in contemporary medical oncology. Moreover, the functional role(s) of vitamin D and its receptors in this tumor remains poorly understood. Therefore, this work offers the unique opportunity to gain mechanistic insight and even to generate a ligand-directed prototype immune drug candidate against this malignant disease.” This work was supported in part by the U.S. Department of Defense IMPACT grant (W81XWH-09-1-0224) and by serial awards from the Gillson-Longenbaugh Foundation and the Susan G. Komen Breast Cancer Foundation (to WA and RP). Source
