Mcl-1 & Lung Cancer
Improving Lung Cancer Treatment with Small Molecules
Lung cancer is the most common form of cancer worldwide. In 2018, 12.3 percent of diagnosed cancer cases were lung cancer cases. “Lung cancer prognosis is very poor. 85% of lung cancer patients survive less than 5 years,” says Xingming Deng, MD, PhD, Professor and Chair in Cancer Biology in the Department of Radiation Oncology in the Emory University School of Medicine. Currently, chemotherapy and radiation therapy are the principal means of treating lung cancer. However, according to Deng, most of these therapies have relatively low success rates – less than 15%.
Deng’s research has focused on trying to find more effective treatments for lung cancer, and his team might have found the lung cancer treatment that doctors and patients have been waiting for: Deng’s lab has discovered a small molecule called MI-223, which when combined with existing chemotherapy drugs, can be used to effectively treat lung cancer.
Deng’s discovery of MI-223 comes from his team’s extensive research on the protein Mcl-1 and the role it plays in cancer cells. Deng’s team found that Mcl-1 is overproduced in lung cancer patients – and this overproduction is associated with poorer prognosis. Deng says that this is because Mcl-1 protects cancer cells from chemotherapy drugs that are used to treat lung cancer.
Lung cancer is treated with the help of chemotherapy drugs that that kill tumor cells by preventing DNA replication from proceeding by suppressing a key enzyme called ribonucleotide reductase. By preventing replication from taking place normally, these chemotherapy drugs inflict damage to DNA in the form of double strand breaks, a form of damage that, if not repaired, can kill cells.
Deng’s team, however, found that cancer cells with enhanced Mcl-1 production were able to promote repair of DNA with double strand breaks induced by chemotherapy drugs, thus improving their chances of survival. More double strand breaks, meanwhile, remained in cells that did not express Mcl-1. This led Deng to conclude that the inhibition of Mcl-1 could potentially be used as a treatment for lung cancer, as this inhibition would prevent cancer cells from repairing the damage to their DNA. Deng then screened the these molecules, part of the National Cancer Institute (NCI) small-molecule library, for their ability to bind to and inactivate Mcl-1 and, in the process, were eventually able to identify MI-223.
The small molecule MI-223, Deng says, “synergizes with” chemotherapy drugs. MI-223 binds to Mcl-1 and prevents it from activating the pathway that cells use to repair double strand breaks, nullifying the advantage that the overexpression of Mcl-1 gives tumor cells. Coupling the small molecule MI-223 with chemotherapy drugs not only inflicts DNA damage, but also prevents tumor cells from repairing this damage, and thus helps slow the growth of tumor cells.
Sean Kim, the case manager of the technology at OTT, says that Deng seems to have a “sixth sense about selecting a target for suppressing the growth of cancer cells.”
“[Dr. Deng] saw what Mcl-1 does in cancer cells that no one else saw and found a novel mechanism that can be manipulated in slowing down the cancer cell growth. It is very exciting to even imagine what he might find next,” remarks Kim.
Deng hopes to develop more targeted drugs – potentially a drug that is “a better Mcl-1 specific drug.” Routine chemotherapy drugs, Deng says, have many side effects, and Deng hopes that developing targeted drugs such as the Mcl-1 inhibitor MI-223 will reduce these.
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