" ferrodemortem " is a newly discovered form of cell death in recent years and has been widely concerned in tumor biology research and clinical treatment. Hydomain Affiliated Cancer Hospital Hydomain Surgery Department Hydomain Hydomain Hydomain Hydomain Hydomain typing" of triple-negative breast cancer is more active in the luminal androgen receptor type (LAR), a subtype of the "Fudan type" of triple-negative breast cancer. Glutathione metabolism with "glutathione peroxidase 4" (GPX4) as the core plays an important role in the regulation of "ferrodemortia" in LAR-type triple-negative breast cancer. GPX4 inhibitor combined with immunotherapy may become a new therapeutic strategy for LAR-type triple-negative breast cancer. The research results related to were published online on October 17 in the top international metabolic journal Cell Metabolism (Journal Impact Factor 31.4). This is the third time the team has published a review in this international top journal in the past two years.
metabolism-immune perspective explores a new strategy for precise treatment
triple-negative breast cancer is a member of the big family of breast cancer . Compared with other subtypes, it has high heterogeneity, poor prognosis, and high risk of recurrence and metastasis, so it has become a stubborn "fortress" that needs to be conquered in breast cancer research. Since 2019, Professors Shao Zhimin and Professor Jiang Yizhou have led a team to carry out a series of research on triple-negative breast cancer. From the proposal of "Fudan classification" to the implementation of FUTURE series of precise treatment clinical trials, the team has successfully increased the objective response rate of advanced triple-negative breast cancer patients with ineffective multiline treatment from 10% to 29%, improving the prognosis of triple-negative breast cancer patients.
However, "Fudan classification" still needs to be improved. Some triple-negative breast cancers in , such as LAR molecular subtypes, are not very sensitive to existing precise treatment strategies, and is still a treatment problem in triple-negative breast cancer. To this end, Professors Shao Zhimin and Professor Jiang Yizhou have led the team in recent years to continuously deepen the "Fudan classification" from multiple angles such as protein , metabolism, immunity, and microbiology, and explore new therapeutic targets, hoping to break through the treatment bottleneck of some triple-negative breast cancer subtypes.
large sample data shows the characteristics of "ferrodemort" for triple-negative breast cancer cells
"By the early improvement of the "Fudan typing" of triple-negative breast cancer, we have confirmed that treatment plans from the perspective of metabolism and immunity may bring significant benefits to the precise treatment of triple-negative breast cancer." Professor Shao Zhimin said that "ferrodemort" is a regulatory cell death method closely related to metabolism discovered in recent years, and is active in the field of tumor research. The team tried to start from this perspective to discover a new breakthrough in the treatment of triple-negative breast cancer. Among the "fragmental death" of
cells, "iron death" is one of them. is named because this form of death is driven by "iron-dependent lipid peroxidation" and is regulated by multiple metabolic pathways. Through large sample transcriptome and metabolomic data, the team first systematically analyzed the ferrody symptoms of triple-negative breast cancer.
study found that cellular metabolic pathways and metabolites related to "ferrodemort" are highly active in LAR breast cancer, suggesting that it may be the subtype that is most sensitive to "ferrodemort". On the other hand, glutathione metabolism with GPX4 as the core is significantly upregulated in the LAR subtype, which is the main way for this subtype to escape "iron death".
researchers found through further mechanism research that androgen receptors (ARs) are the key factors in regulating LAR subtype ferrodys. However, the regulatory effect of AR on "ferrodemortia" in triple-negative breast cancer is positive and negative, which can not only promote the expression of GPX4 to help tumor cells escape "ferrodemortia", but also increase the synthesis of unsaturated lipids related to "ferrodemortia". This may partly explain the poor efficacy of AR receptor inhibitors in clinical trials in the treatment of LAR-type breast cancer.
GPX4 inhibitor combined with immunotherapy may become a new target for treatment
team further utilizes mouse models, organoid models and retrospective clinical trial data to explore the clinical value of targeting "ferrodemortem" in the LAR subtype. results found that GPX4 inhibitors can not only inhibit tumors by promoting "ferrodemortem", but also reshape the tumor immune microenvironment, and causes LAR subtype tumors to "cold" and "hot".The combination of GPX4 inhibitors and immunotherapy can further activate T cells in the tumor microenvironment, and the efficacy of dual-drug therapy is significantly higher than that of single-drug therapy. This result shows that the combination of targeted ferrodystrophy and immunotherapy may be a new direction for precise treatment of LAR subtype breast cancer.
"This study is a further expansion of our triple-negative breast cancer research system, and the research model is also very novel." Professor Jiang Yizhou said that the research starts from key clinical issues, chooses novel perspectives, and combines solid experimental demonstration to finally return to clinical treatment.
"Focusing on key clinical scientific issues and carrying out research that is truly useful to patients is Professor Shao's consistent requirement for us." Dr. Xiao Yi said, "As the younger generation, I am fortunate to stand on the 'shoulder of a giant' and continuously expand the depth and breadth of precise treatment of triple-negative breast cancer, and hope to bring good news to more patients."
Author: Tang Wenjia Wang Guangzhao
Editor: Tang Wenjia
Source: Interviewed Party
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