BarcelonaTumors can be cold or hot depending on the immune system's ability to attack them. Quite simply: some types of cancer, such as skin cancer, are classified as hot cancers because the defenses deploy a cordon to contain their spread. This defense measure – which is also triggered in the face of infection – makes patients potential beneficiaries of immunotherapies, a strategy by which the immune system is stimulated against malignant cells. But there are other cancers, such as small cell lung cancers, that are called cold tumors because this system is out of play: defenses are inhibited and not activated against the tumor. Now, what if the immune ability of cold crabs could be genetically modified to behave like warm crabs?
This is the main line of research of Israel Canidas (el Prat de Llobregat, 1984), assistant professor of the Research Program in Nuclear Dynamics and Cancer at Fox Chase Cancer Center, in Philadelphia. As the leader of a group specializing in the study of tumor immunity and the microenvironment in lung cancer, the Catalan scientist – who trained at the Hospital del Mar Institute for Medical Research (IMIM) and the Dana-Farber Cancer Institute – Harvard Medical School – has identified a mechanism that makes cold tumors more vulnerable to immune attacks.
Cañadas's research focuses on small cell lung cancer, a highly aggressive and deadly cancer: it accounts for 15% of all lung tumors, and the five-year survival rate stabilizes at about 5%. “In general, cold cancers are more aggressive and less susceptible to treatment, especially immunotherapy, and small cell lung cancers are the classic example,” Cañadas explains in a video call.
The team leading the Catalan Fox Chase used a technique called viral mimicry – which has aroused great interest in the scientific community – which consists in stimulating a reaction in cancer cells similar to that which occurs in front of a virus. In this case it is not necessary to use the pathogen, but the goal is to attract… Attention the immune system so that it can detect and attack the tumor.
To do this, Cañadas performed genetic screening of cell lines from patients with small cell lung cancer until he found the key: the DHX9 gene. This element allows RNA or DNA strands to be separated to facilitate cell proliferation and is overexpressed in tumors. Based on this result, the study achieved a dual goal: deleting the gene activates immune signaling and significantly reduces the number of cancer cells.
Success in mice
The genomes of many viruses and bacteria that normally infect our cells consist of double-stranded RNA, and the body's cells are equipped with innate mechanisms to recognize them. They are sensors that start the process of sending signals to destroy the virus. The process that reproduces this behavior so that the immune system is activated and cancer cells are filled with defenses, as happens with viral cells, is called viral mimicry. Once the DHX9 gene is removed, the cancer cell secretes cytokines — small proteins that activate the immune system — and defenses can recognize and attack the tumor.
The researcher also noted that deleting this gene causes the accumulation of large toxic amounts of DNA-RNA hybrids called R-loops inside the cancer cell. “Our body already knows how to get rid of them, but by eliminating DHX9, the substance is damaged and disappears.” Cancer cells die quickly, Cañadas explains. His team tested this benefit on mice with small cell lung cancer, and confirmed that there were signs that the animals' immune systems recognized and attacked the tumor, and that the growth and size of the cancer decreased significantly.
By eliminating the DHX9 gene, tumors die faster.
“The survival rate of mice is very low, like the survival rate of humans, but it increased dramatically. In fact, we only ran the experiment for two months for ethical reasons and we had to sacrifice them because they were still alive,” says Cañadas, who describes The results are exciting and surprising. The discovery was published in Cancer detection, a journal of the American Association for Cancer Research (AACR), opens the door to the development of the first drugs that will make immunotherapy effective for small cell lung cancer. “We think it can also be applied to other types of cancer,” he predicts.
The researchers are already collaborating with the pharmaceutical company Accent Therapeutics, which has designed a drug that inhibits DHX9. “We met by chance at the annual meeting of the AACR, one of the largest cancer research conferences, in April, and I already had the drug in my lab to begin testing. in the laboratory“Canadas says.
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