Telomere-lengthening molecule could be treatment-resistant cancer's Achilles heel

Alternative lengthening of telomeres cells, or ALT cells, have long presented a challenge for researchers and oncologists alike. Unlike other cancer cells, which use the enzyme telomerase to lengthen their telomeres and grow indefinitely, ALT cells don’t possess telomerase. Instead, these treatment-resistant cells have other means of keeping their telomeres from degrading.  

Now, a team of researchers from Portugal’s Instituto de Medicina Molecular João Lobo Antunes reported Monday that it has found the RNA molecule involved in preserving telomere length in ALT cells could perhaps be used against them.

The molecule, called telomeric repeat-containing RNA, or TERRA, is present in low levels in normal cells but is far more abundant in ALT cells. There, it causes controlled DNA damage that is then repaired in a process called break-induced telomere synthesis, or BITS, ultimately increasing the telomeres’ length. But it appears there is a limit to how much damage ALT-cell telomeres can handle: The research team found that when TERRA levels were expressed beyond a certain level, the cells would stop dividing and die.

“When the levels of TERRA are increased, the damage at telomeres also increases and this becomes so heavy that even a cancer cell that is usually more resistant is not able to multiply anymore,” first author Bruno Silva, Ph.D., a senior postdoctoral researcher at the institute, said in a release.

The study builds upon the team’s previous work on TERRA, where they developed a first-of-its-kind molecule to inhibit its transcription and ultimately reduced DNA damage to ALT cell telomeres, impairing their elongation.

In their newest study—published in the Proceedings of the National Academy of Sciences—the researchers looked at what would happen if they did the opposite, using molecular tools to overexpress TERRA in ALT cells. They hypothesized that there might be a threshold beyond which damage to a cell’s telomeres would be too much for repair mechanisms to keep up with.

This turned out to be the case: High levels of damage by TERRA overwhelmed the usual DNA repair mechanisms so much that the cells needed to recruit other telomeres to help. This led to the loss of multiple telomeres at once and stunted the cells’ division.

Together, the results of the researchers’ previous work and their new study suggest that TERRA might be a “uniquely versatile” therapeutic target, Silva said.

“By decreasing its levels we can block telomere maintenance, as we have shown before, while by increasing TERRA levels, we can rise the damage to levels that are not sustainable even for a cancer cell, eventually leading to cell death,” he said.

The team is currently in the process of identifying the proteins that activate or inhibit the expression of TERRA. From there, they plan to develop small molecules targeting those factors and test them out against ALT cancer cells, Silva told Fierce Biotech in an email. 

While a number of telomerase inhibitors have been developed to treat various types of cancer—such as Geron’s imetelstat, Invectys’ cancer vaccine INVAC-1 and riavax, another cancer vaccine from Korean firm GemVax & Kael—drugs targeting TERRA have not yet been developed.