Newswise — Los Angeles, September 2021) –The Cedars-Sinai researchers discovered key components that control telomerase reverse transcriptionase (or TERT) expression. This is one of the essential component proteins of Telomerase. Many cancers have high levels of TERT. This is due to mutations in DNA which control TERT levels in cells.
Targeted therapies to impede telomerase have been tested in clinical trials. However, these trials have been largely unsuccessful. Dan Theodorescu MD, PhD, is the director of Cedars-Sinai Cancer, and the corresponding author of the study. 13 The Proceedings of the National Academy of Sciences . The research was done in both laboratory mice and in human cells.
“Teleomerase inhibitors have been difficult to develop, as this protein complex is critical in normal stem cells and progenitor cell lines,” Theodorescu stated. Progenitor cells are the descendants of stem cells, which create specialized cells. “In this study we tried to find a way to block telomerase levels that are driven by mutations only found in cancer cells. This work was based on bladder cancer, but could be applied to other types of cancers that have similar mutations. “
Using a CRISPR-based functional genome screening and reporter system, investigators discovered that TRIM 28,, which converts DNA into RNA, activates TERT. TERT expression is repressed by another protein, TRIM 24,. These two proteins interact and TRIM 24 grabs onto the TRIM 28 protein and stops it from making TERT. This reduces telomerase activity, and helps to stop cancer cell proliferation.
Researchers also discovered that mTORC1 (a third protein) can activate TRIM 28 through a modification known as phosphorylation. This prevents TRIM 28 and TRIM 24. from interfacing. This allows TERT to become expressed and activates telomerase.
The investigators found that Ridaforolimus suppressed the activity of mTORC1, activating TRIM 28 and inhibiting the growth and activation of TERT.
“Additional, specific inhibitors of mTORC1 such as Ridaforolimus, or direct inhibitors of TRIM28 interactions with mutant TERT promoter, may provide treatment options to prevent telomerase from allowing cancer cells to grow in cancer patients with TERT promoter mutations,” Theodorescu said. We hope this study will lead to new telomerase-directed treatments for cancer. This is possible by laying the conceptual framework, and using innovative tools to demonstrate that promoter mutations-directed therapy may be possible. “
Research reported in this study was supported by the Colorado Clinical and Translational Sciences Institute, under NIH Award Number UL1TR001082; the Cancer Foundation of Luxembourg; and the Department of Defense Congressionally Directed Medical Research Program, under Award Number CA10175.
Read more about cancer clinical trials on the Cedars-Sinai Blog: Common Questions About Cancer Clinical Trials
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