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Usually, scientists study the molecular biology of cancer to find new treatments, but sometimes it is different: when they try to find new treatments, they find key information about the biology of cancer. Researchers at the National Telomeres and Telomerases Research Group at the National Cancer Research Center (CNIO) have identified new drug combinations that inhibit resistance to treatment in mice with glioblastoma, the most malignant brain tumor. They also discovered an unexpected link between the RAS pathway, implicated in many types of cancer, and telomere maintenance. This discovery, which could be used in new areas of research, will be published in the medical journal EMBO molecular medicine.
We had a double result in our study. We were looking for approved drugs that could block a new target and we found them. During the process, we also found that certain molecular pathways that play a role in cancer development also participate in the regulation of telomere maintenance. This is an interesting aspect of cancer biology that was previously unknown. "
Maria A. Blasco, Head of CNOM's Telomeres and Telomerase Group and Director of the CNIO in Madrid
For this reason, scientists who participated in the study decided to label it "Several cancer pathways regulate the protection of telomeres".
TRF1 as target in cancer stem cells
Telomeres are protective structures located at the ends of chromosomes. The CNIO telomere and telomerase group discovered that attacking telomeres in cancer cells could be an effective strategy for stopping cancer growth. In particular, researchers in this group found that the inhibition of telomer TRF1 inhibits tumor progression in human and murine glioblastoma models.
Glioblastoma is the most common brain tumor, with an average survival time of about 14 months. It can be difficult to treat because it contains a population of cancer stem cells that can regenerate an entire tumor. Two years ago, CNIO researchers discovered that glioblastoma cells have high levels of TRF1, a protein whose expression in stem cells is increased. They tried to block this protein with compounds developed at the CNIO and the strategy was effective because it increased the life expectancy of mice with glioblastoma by up to 80%.
Considering that glioblastoma treatment often fails due to the high resistance of these tumors to conventional therapies, Telomere and Telomerase researchers have been looking for other TRF1 inhibitors among previously approved compounds for the treatment of cancer or cancer. drugs used in clinical trials. The study will be published in EMBO molecular medicine this week.
A new role for anticancer drugs in use
CNIO researchers have searched for TRF1 inhibitors among the 114 anticancer drugs available for well-known cancer pathways. Screening revealed that a number of these drugs could block TRF1 in glioblastoma and lung cancer cells.
Interestingly, the mechanisms of action of these drugs covered molecular pathways closely related to cancer, such as components of ARS, and independent of the first inhibitors developed at the CNIO (Bejarano et al., Cancer Cell, 2017).
"The fact that there are several telomere protection pathways acting on TRF1," says Jessica Louzame, co-author of the article, confirms the importance of telomeres for cancer cells. Their identification will allow us to find new ways to attack telomeres and fight against cancer Our group is a pioneer in the study of this innovative strategy. "
More drug combinations for less resistance to treatment
After identifying drugs capable of blocking TRF1, CNIO researchers went one step further by testing a combination of these drugs with the first TRF1 inhibitors developed at the CNIO.
The efficacy of the drug combinations has been tested in mouse models of human glioblastoma and has shown promising results. The drugs had beneficial synergistic effects and helped overcome resistance to treatment.
"Our work shows that combinations of TRF1 inhibitors could become an effective strategy for inhibiting cancer growth and fighting drug resistance," said co-author, Giuseppe Bosso.
Source:
National Center for Cancer Research (CNIO)
Journal reference:
Blasco, M.A. et al. (2019) Several cancer pathways regulate the protection of telomeres. EMBO molecular medicine. doi.org/10.15252/emmm.201910292.
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