Science: targeted pyrimidine synthesis enhances the molecular therapeutic response of glioblastoma stem cells

August 11, 2019 / bioin / - glioblastoma is a kind of malignant brain cancer that invades the surrounding brain tissue, and the surgical treatment is extremely difficult Even if chemotherapy and radiation successfully destroy most of the glioblastoma cells in patients, they may not affect cancer stem cells This small group of tumor cells has the ability of infinite growth and reproduction, and can lead to tumor recurrence To study the tumors and test new treatments, researchers at the University of California San Diego School of medicine used mice with samples of glioblastoma tumors donated by surgical patients In this way, they recently found that combination of targeted cancer therapy and multiple sclerosis (MS) drug telifloxane treatment can block glioblastoma stem cells, significantly reduce tumor size and improve mouse survival rate The study was published in Science Translational Medicine on August 7, 2019 Photo source: UC San Diego School of medicine "we used to think that we would find a magic bullet to treat every glioblastoma patient," said Jeremy rich, Professor of medicine, director of neurooncology, director of the Institute of healthy brain oncology, University of California, San Diego School of medicine "But now we realize that we need to find out the cause of each patient's unique tumor and tailor the treatment for each individual "In recent years, the desire for personalized cancer therapy has led to the development of several targeted cancer therapies These drugs work by inhibiting specific molecules on which cancer cells depend for growth and survival Therefore, compared with traditional therapies (such as chemotherapy and radiotherapy), targeted therapy has better effect and fewer side effects However, targeted therapy has not been as successful as the scientific community had hoped Rich believes that's because it's usually not enough to inhibit a molecule or pathway that drives tumor formation or survival - cancer cells will find a way to compensate "As scientists, we often look at what cancer stem cells are doing," rich said As a clinician, I also try to see things from a larger perspective I'm not just looking for one or two drugs to help my patients, because I think that really killing cancer cells requires a lot of personalized combinations of different drugs "In order to continue to replicate, glioblastoma stem cells need to make more DNA, and to do that, they need to make pyrimidine, which is one of the components of DNA Rich's team mined tumor genome data from six different databases from hundreds of glioblastoma patients and found that the higher the pyrimidine metabolism score, the lower the survival rate of patients "It takes a lot of effort to become a cancer cell They must always strive to find ways to connect the path of survival and growth I don't care about them But knowing this helps us understand where their weaknesses are "Ms drug telifloxamide just blocked pyrimidine forming enzyme Rich and his team found in the lab that terfluramine inhibited the survival, self-renewal and tumorigenesis of glioblastoma cells What's more, the researchers found that when treated with tertiazem alone, the tumors produced by the patients were slightly smaller and the survival time of the mice carrying the tumors was longer than that of the mice receiving the simulated treatment The team also tested two targeted cancer therapies: bkm-120 and lapatinib Bkm-120 is an inhibitor, which works best in glioblastoma cells lacking PTEN enzyme; lapatinib is an inhibitor, which is used to treat EGFR mutation driven cancer When bkm-120 was used alone, the tumor was moderately reduced and the survival time of mice was longer than that of mice treated with simulated therapy or tertiazem However, compared with the mice receiving the simulated treatment and the mice receiving the two treatments alone, the tumor was significantly reduced and the survival time of the mice was significantly prolonged "We are excited about these results, especially because we are talking about a drug that is known to be safe for humans," rich said But this lab model is not perfect -- yes, it uses samples from human patients, but it still lacks the environment of glioblastoma in human body, such as the interaction with the immune system, which we know plays an important role in determining tumor growth and survival Before the drug can be used in patients with glioblastoma, human clinical trials are needed to support its safety and effectiveness "Reference: Xiuxing Wang et al Targeting pyrimidine synthesis accesses molecular therapy response in glioblastoma stem cells, Science Translational Medicine (2019) Doi: 10.1126/scitranslmed.aau4972