As normal human cells age and lose the ability to divide further, some of the damaged cells may enter senescence, a zombie-like state of "living death." Although senescence can be harmful to the body, keeping cells in this state can help prevent them from progressing to malignancy and cancer. For example, when cells are infected by viruses or suffer mutations and activate oncogenes, most will age rapidly and enter senescence. However, when pre-malignant cells undergo additional changes and reactivate the enzyme telomerase reverse transcriptase (TERT), they can escape senescence and progress to cancer.
In a collaborative study of mice published recently in the journal Cell Chemical Biology, University of Chicago cancer biologists found that blocking a certain enzyme can prevent cells from escaping senescence. Combined with radiation, inhibiting TERT holds promise as a potential therapeutic option to treat cancers.
TERT as a cancer target
TERT helps cells resist senescence by serving as the enzymatic component of telomerase. TERT expression is normally restricted to stem cells, where it helps maintain the telomere caps at the ends of chromosomes. As cells differentiate, TERT is repressed and telomeres will then begin to shorten with each cell division.
When cancer cells reactivate TERT, the telomere caps remain protected as cells divide, making them immortal. Because nine in 10 tumors express TERT, many scientists wondered if the enzyme might be cancer's long-sought Achilles heel. However, treating cancer patients with drugs to inactivate TERT has historically failed, as most cancers would not only survive but could continue to grow and spread even without telomerase. Interest in TERT as a target for cancer therapy has since waned.
In 2020, an interdisciplinary team of researchers at UChicago, Northwestern University, and the University of Sydney in Australia reported a novel drug, NU-1, that irreversibly blocks TERT enzyme activity in cancer cells.
The new research does more than simply target cancer cell immortality. Senior author Stephen Kron MD, PhD, Professor of Molecular Genetics and Cell Biology at UChicago, explained that along with protecting telomeres, TERT expression also confers other features of stem cells, including greater tolerance for many kinds of stress, such as DNA damage. This has long suggested that TERT may contribute to cancer's resistance to conventional, DNA-damaging treatments like chemotherapy and radiation. The team asked whether their TERT inhibitor might improve the ability of radiation to treat cancer in mice. This led to a surprising result and a promising new strategy to treat cancer patients.
Finding synergy between treatments
Although advances in targeted therapies and immunotherapy have benefited many patients, radiation and chemotherapy remain the best treatment options for most cancers. These therapies can shrink tumors by directly killing cancer cells, but even heavily damaged cancer cells may survive and return to growth. TERT may be partly responsible for the cells' abilities to resist the direct effects of chemotherapy and radiation. Indeed, treating human cancer cells with NU-1 or other TERT inhibitors made chemotherapy agents and radiation more toxic. TERT inhibitors blocked DNA repair in irradiated cancer cells. Interestingly, surviving cancer cells responded to the unrepaired DNA damage by entering senescence rather than growing.
“Of course, turning radiation into a local anti-tumor vaccine has been talked about before,” Kron said. “However, we may now have a safe and effective way to do it. If this strategy also works in humans, then we're off to the races.”
While the anti-tumor immune response stimulated by therapy has the potential to eliminate tumors, it is often temporary and ineffective. This new work points to TERT as a key factor that helps cancer resist both the direct and indirect effects of chemotherapy and radiation by repairing the damage and evading the immune response, allowing the tumor to return to growth. “There’s over a half million cancer patients treated with radiation each year,” Kron said. “Let's try to have more of those be cures.”
TERT inhibition retains immune responses in tumors
Although the Cell Chemical Biology paper does not introduce any completely new concepts, it has potential for real-world impact by offering a tumor-specific way to induce an increased anti-tumor immune response after radiation. Considering the potential impact of blocking TERT on immune responses after radiation, Kron and his colleagues examined whether blocking TERT with NU-1 treatment might make tumors in mice more sensitive to radiation. While prior studies using TERT inhibitors had shown modestly enhanced effects of radiation on human tumors, the tumors continued to grow in immunodeficient mice, preventing evaluation of the effects on anti-tumor immunity.
Here, using mouse colon cancer tumors implanted in otherwise normal mice, treating with NU-1 had no effect on its own, but allowed a single dose of radiation to eliminate tumors. By contrast, radiation alone caused tumors to shrink, but they soon returned to growth. Microscopy analysis of the tumor tissue revealed that radiation alone could only produce a short-lasting immune response while the combination with NU-1 encouraged the immune cells to remain in the tumor and target the cancer cells.
This puts reactivation of TERT in a new light, as providing another means by which cancer cells may evade the immune system as tumors form and spread and then limit and survive the harmful effects of therapy. Members of the team have co-founded Riptide Therapeutics, a spin-out from the University of Chicago and Northwestern University. Their goal is to advance TERT inhibitors for cancer treatment based on these preclinical discoveries.
Potential for clinical translation
NU-1 or related TERT inhibitors will not be appropriate for every cancer patient, but the team hopes to develop companion tests to identify which patients are most likely to benefit. Along with confirming that the tumors express TERT, other tissue markers used to select immunotherapy may predict success.
The study, “Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization,” was supported by the National Cancer Institute R01s CA217182, CA199663 and Specialized Program of Research Excellence (SPORE) P50 CA159981, METAvivor, and the Chicago Biomedical Consortium. Additional authors include Yue Liu, Joanna Pagacz, Elena Efimova, Ding Wu, and Donald Wolfgeher from University of Chicago; Rick Betori, Grant Frost, Karl Scheidt from Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Tracy Bryan, Scott Cohen from University of Sydney, Australia. NU-1 is protected by a U.S. patent assigned to Northwestern University.