In 2004, a group of researchers from Princeton University identified a gene involved in the development of metastatic breast cancer: methadherin, or MTDH. By focusing their research on this single gene in two new studies, American scientists managed to neutralize it to prevent the development of cancer cells.
Metastatic cancer is the appearance of cancer cells in other parts of the body other than the original tumor. This is one of the main areas of interest for researchers, as it is the main cause of death from this disease. “Metastatic breast cancer causes more than 40,000 deaths annually in the United States, and patients respond poorly to standard treatments such as chemotherapy, targeted therapy and immunotherapy,” explains Minhong Shen, a member of the Princeton team behind the new discovery.
Although surgery or chemotherapy may be effective in eliminating the original tumor, the separated cells that cause metastases can safely enter the body and give rise to new tumors months or even years later.
Princeton University researchers working in this field have been doing some work for more than 15 years, focusing on one gene that plays a central role in the ability of most large cancers to form metastases: methadherin (MTDH). Discovered in a 2004 study, Yibin Kang and his team then showed that this gene was amplified and produced abnormally high levels of MTDH proteins in about a third of breast tumors, and that it plays a central role in the metastasis process and in the resistance of these tumors to chemotherapy.
Scientists explain that MTDH is involved in the development of cancer in two main ways: helping tumors cope with the stress of chemotherapy and drowning out the alarm signal that organs usually give when a tumor invades them.
“In most major human cancers, this gene is necessary for cancer progression, but it does not seem to be important for normal development,” explains Yibin Kang. “In normal tissues, healthy cells are usually not stressed or do not transmit signals that the immune system can recognize as foreign, so MTDH is not important for normal tissues. In fact, MTDH is the quintessence of the “cancer fitness gene”, which is extremely necessary for malignant cells to survive and thrive.” So, in subsequent studies, mice without the MTDH gene grew normally, and mice with breast cancer without this gene had much fewer additional tumors. More importantly, the tumors that did form did not metastasize in the same mice.
To counteract the metastatic effect of the gene, the researchers analyzed its crystal structure and principle of action. Their experiments showed that MTDH depends on another protein called SND1, with which it forms a complex. By interacting with SND1, MTDH prevents the immune system from recognizing the danger signals normally generated by cancer cells, thereby preventing it from attacking them. The newly found compound activates the body’s alarm system.
Now researchers are working on improving the compound, hoping to increase its effectiveness in disrupting the connection between MTDH and SND1 and reduce the required dose. They hope to be ready for human clinical trials within two to three years.