The Means to an End of Aggressive Tumors

After five years of work, a project led by Columbia University scientists has revealed a key weakness in some of the most aggressive and treatment-resistant cancers, including gliomas and pediatric sarcomas. The findings, published in the journal Genes & Development, identify a protein that these tumors depend on for survival, which the team is now working to target with effective therapies.

In normal cells, successive rounds of DNA replication shorten the ends, or telomeres, of chromosomes. After enough rounds of cell division, this cumulative genome damage can stop cell growth. When cells escape this aging process, they can keep dividing forever, a key event enabling the development of tumors. “They do that by maintaining the stability of the telomeres, using mechanisms that are not shared by normal, healthy cells,” says Angelo Taglialatela, PhD, an associate research scientist in the department of genetics and development at Columbia and lead author on the new paper.

A different way to stay immortal

Most cancers produce an enzyme called telomerase to maintain their telomeres. A few, however, rely on an alternative mechanism known as ALT (alternative lengthening of telomeres), which uses the cell's DNA repair machinery to maintain telomeres. “We were fascinated by this smaller fraction of human tumors, but our main question was can we use our knowledge of the ALT pathway to identify specific vulnerabilities for these tumor types?” says Taglialatela.

It’s a critical question for patients. “Currently there are no therapies available for these ALT-positive tumors, so it’s really an unmet need,” says Alberto Ciccia, PhD, professor of genetics and development at Columbia and a member of the Herbert Irving Comprehensive Cancer Center (HICCC). For patients with ALT-positive cancers, including many aggressive gliomas and pediatric sarcomas, treatment options remain limited. By uncovering a critical weakness in this pathway, the study opens the door to a new approach for targeting these otherwise difficult-to-treat tumors. To identify that weakness, Taglialatela, Ciccia, and an international team of collaborators took a deep dive into the ALT pathway and the proteins it depends on.

Uncovering a critical vulnerability

The researchers began with a computational analysis of more than a thousand cancer cell lines whose molecular characteristics had already been mapped. “Among all the protein-coding genes, we identified SMARCAL1 as the top dependency in these tumors compared to other tumor types,” says Taglialatela. Previous work had identified SMARCAL1 as a component of the DNA replication and repair machinery, so it made some sense that ALT might need it. But it wasn’t obvious how this protein contributed specifically to ALT-positive tumors. “It took almost five years to elucidate the mechanism,” says Taglialatela.

Through an extensive series of genetic, biochemical, and microscopy-based analyses, the investigators uncovered a complex but vulnerable system.  

“ALT is a recombination-dependent process that utilizes telomeric sequences from other chromosomes or sister chromatids to enable the elongation of a telomere,” says Ciccia. In essence, ALT mixes pieces of DNA together from different parts of the genome to rebuild and maintain telomeres. This genome hacking operates in a delicate balance, though, and SMARCAL1 regulates it. Without SMARCAL1, ALT undergoes excessive activation that damages telomeres instead of preserving them.

Turning a survival mechanism against cancer

“We propose that SMARCAL1 works as a brake to maintain controlled activation of the ALT pathway. In the absence of SMARCAL1, ALT becomes hyperactivated, leading to uncontrolled telomeric DNA processing that ultimately derails the pathway and compromises cancer cell growth,” says Taglialatela, adding that “what gives these cancer cells their survival advantage can then be turned into a vulnerability." Without that control, the cancer cells lose their ability to maintain their telomeres and ultimately enter senescence, a state in which they stop dividing.

Recent cancer drugs called senolytics work by killing senescent cells, and inactivating SMARCAL1 could make those compounds effective against otherwise untreatable ALT-dependent cancers. Ciccia’s lab is already pursuing that strategy. “We recently obtained a grant from the HICCC’s Irving Cancer Drug Discovery Program to develop inhibitors targeting SMARCAL1,” says Ciccia. So far, the team has identified several lead compounds that they are now working to characterize and improve.

Though the researchers caution that the drug development project is still at its earliest stages, they’re optimistic about its potential for cancer therapy. “Normal cells don't rely on this pathway; only cancer cells do. That means targeting this pathway can provide specificity toward the cancer cells,” says Ciccia.