2024-01-10 05:24:12
A domestic research team has discovered the principle of anticancer drug resistance in ‘undifferentiated thyroid cancer’, which has an average survival time of less than one year. It is expected that a new treatment strategy may be developed in the field of undifferentiated thyroid cancer.
Gangnam Severance Hospital announced on the 10th that the research team of Professor Seongsun Hwang of the Department of Biomedical Sciences at Yonsei University College of Medicine, Seokmo Kim, and Hyukjun Yoon of the Department of Thyroid and Endocrine Surgery at Gangnam Severance Hospital identified the anticancer drug resistance mechanism of undifferentiated thyroid cancer that shows high resistance to existing anticancer drugs.
Professor Seong-soon Hwang of the Department of Biomedical Sciences at Yonsei University College of Medicine, and Professors Seok-mo Kim and Hyuk-jun Yoon of the Department of Thyroid and Endocrine Surgery at Gangnam Severance Hospital. (From left) Photo: Gangnam Severance Hospital
Undifferentiated thyroid cancer (ATC) has different characteristics from the most common papillary thyroid cancer (PTC). It is considered one of the most difficult cancers to treat among existing cancers. Although it is rare, accounting for less than 1% of all thyroid cancer patients, once it is diagnosed, the prognosis is poor because it metastasizes quickly. Death can occur within 3 months without treatment. Even with treatment, the survival rate for more than one year is only 20%.
The research team conducted a genome analysis to find the principle of resistance of undifferentiated thyroid cancer to anticancer drugs and confirmed that the expression of glutaminase (GLS) was higher in undifferentiated thyroid cancer compared to papillary thyroid cancer. Cancer cells use glutamine as their main nutrient to survive. Glutamine provides various nutrients and energy to tumor cells by synthesizing glutathione (GSH) using glutaminase (GLS). This is why glutaminase (GLS) is found to be high in major carcinomas.
The researchers predicted that the effectiveness of anticancer drugs would increase if they prevented the supply of nutrients to cancer cells by inhibiting glutaminase (GLS). Contrary to predictions, undifferentiated thyroid cancer cells survived even when the glutamine degradation pathway was inhibited.
In this process, the researchers discovered that undifferentiated thyroid cancer survives by utilizing the ‘single carbon metabolism mechanism’. Afterwards, an animal experiment was conducted in which a glutaminolytic enzyme inhibitor (BPTES) and an inhibitor (CBR-5884) that inhibits PHGDH, a key enzyme in the single-carbon metabolism mechanism, were administered simultaneously.
As a result, it was found that the balance of reactive oxygen species (ROS) that maintains cancer cells was disrupted, promoting cancer cell death. The research team said, “The anticancer effect has improved by regarding 50% compared to using a single existing anticancer drug.”
Images related to thyroid cancer. Photo JoongAng Photo
When only glutaminolytic metabolism was inhibited, cancer cells survived by activating the single-carbon metabolism mechanism, but when glutaminolytic enzyme and single-carbon metabolism were simultaneously inhibited, the oxygen radical balance collapsed, cancer cells died, and anticancer drug treatment efficiency increased. The researchers additionally conducted a genome test and confirmed that the mechanism of single-carbon metabolism becomes stronger as papillary thyroid cancer (PTC) progresses to undifferentiated thyroid cancer (ATC).
Professor Seong-soon Hwang said, “Research on the development of new drugs that inhibit glutamine decomposition and single-carbon metabolism is actively underway overseas, but has not yet received much attention in Korea.” He added, “The single-carbon metabolism mechanism is the most important factor in anticancer drug resistance, so it can be controlled.” “We will continue follow-up research to develop new drugs,” he said.
This study was published in ‘Cell Death & Disease’ by Nature Publishing Group (NPG).
Reporter Hwang Soo-yeon ppangshu@joongang.co.kr
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