PHILADELPHIA (January 12, 2024) — Researchers at Fox Chase Cancer Center have identified a genetic mechanism that can make small cell lung cancer tumors vulnerable to attack by the immune system.
The discovery, which was outlined in a recently published study, could be used to develop drugs that would make immunotherapy effective in small cell lung cancer for the first time. Immunotherapy is a type of treatment that uses the body’s immune system to recognize, attack, and kill cancer cells.
The study, “Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer,” was published in Cancer Discovery, a journal of the American Association for Cancer Research.
“It sensitized these tumors to immunotherapy, which is really promising, especially for small cell lung cancer, which has been quite resistant, in general, to any kind of treatment,” said Israel Cañadas, PhD, an Assistant Professor in the Nuclear Dynamics and Cancer Research Program at Fox Chase and the study’s lead author. It’s a major step toward finding new treatment options for a disease that currently has a five-year survival rate of less than 5%.
Small cell lung cancer causes so-called “cold” tumors that can’t be detected by the immune system. This not only allows them to evade the body’s natural immune defenses, it also makes immunotherapy ineffective.
For the new study, researchers looked at using a technique called viral mimicry to turn these cold tumors “hot,” making it possible for immune cells to detect and target them. Viral mimicry involves inducing a reaction in cancer cells that appears similar to a viral infection, which attracts the attention of the immune system.
Using genetic screening of lung cancer cells, researchers found that a gene called DHX9 suppressed levels of dsRNA, an immune-signaling molecule. This finding was especially interesting, because DHX9 is highly expressed in small cell lung cancer compared to other tumor types.
When researchers genetically depleted DHX9 in the cancer cells in the lab, levels of dsRNA significantly increased and immune signaling was activated. The DHX9-depleted cancer cells also accumulated large amounts of DNA-RNA hybrids called R-loops. When researchers took a closer look, they saw that these molecules were damaging the DNA of the cancer cells.
“We saw a very dramatic decrease in cell viability,” Cañadas said. “After knocking out DHX9 in the cancer cells, the cells died very quickly.”
“We saw a very dramatic decrease in cell viability. After knocking out DHX9 in the cancer cells, the cells died very quickly,” said Cañadas, who is also a member of the Cancer Epigenetics Institute and the Center for Immunology at Fox Chase.
Importantly, the DNA damage didn’t occur in healthy cells. Only the cancer cells died, he noted. The Fox Chase research team then tested their findings in mice. They found that when they genetically depleted DHX9 in mice with small cell lung cancer, tumor growth significantly decreased in the animals. They also found signs that the animals’ immune systems were recognizing and attacking the cancer cells.
A follow-up study looked at combining DHX9 depletion with immunotherapy. “The tumors almost disappeared and survival dramatically increased in the mice,” said Cañadas, who called the results “exciting.”
“We were surprised,” he said. “We were expecting some response, but it was really dramatic.” Researchers are now partnering with a pharmaceutical company on the development of a DHX9 inhibitor. “Our objective and dream will be to move this therapy to patients and see if this is a therapy that can work for small cell lung cancer and other cold tumors,” Cañadas said.
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