Research News

A Cleveland Clinic-led team of researchers has discovered how drugs can be repurposed to treat small cell lung cancers (SCLC) that resist standard high doses of chemotherapy and immunotherapy. Their findings are published in Cell Reports. 

SCLCs resist chemotherapy, radiation therapy and immunotherapy and are therefore some of the most lethal cancers. Chemotherapy and radiation therapy aim to damage the DNA of the cancer cells to activate their self-destruction programs. Unfortunately, SCLCs genetically delete the master switch that allows them to sense damage and self-destruct. 

“Meanwhile, the self-destruct switch is intact in normal cells. So even as the cancer cells survive, these treatments continue to induce normal cells to die,” says Yogen Saunthararajah, MD, Translational Hematology and Oncology Research. “We therefore need new ways of treating cancer that don’t rely on an absent self-destruct mechanism.”  

SCLC cells are cells that became “lost” on their developmental journey into neuroendocrine cells. Dr. Saunthararajah’s team, led by first author Sudipta Biswas, PhD, discovered a key mechanism underlying this inability of the SCLCs to complete the transition into normal neuroendocrine cells:  the genes necessary for the final specialized cell state remained packaged away, and thus could not be “turned on.”  

They also found that a key enzyme called DNMT1 keeps these genes “off” by attaching a molecule called a methyl group directly to DNA. DNA physically coils up in response, folding over genes that would normally be exposed and making them inaccessible.  

“Now that we know how the SCLC cells came to be cancer cells instead of normal neuroendocrine cells, we know what to do to allow them to resume their intended journey,” says Dr. Saunthararajah. “This approach is one of fixing or repairing, rather than trying to activate self-destruction.”

New uses for approved drugs 

DNMT1-inhibiting drugs are already used treat blood cancers. A challenge when trying to use the same drugs to treat SCLC is that they are much better at entering blood cancer cells than SCLC or other cancer cells. The team had to devise strategies to enhance these drugs’ activity and entry into SCLC cells in lungs, liver and other tissues where they spread. They were able to achieve this by alternating two different DNMT1-inhibiting drugs used to treat blood cancers, decitabine and 5-azacytidine, and combining these with a third FDA-approved drug called teriflunomide, commonly used to treat multiple sclerosis. A fourth drug, called tetrahydrouridine, was also necessary. Tetrahydrouridine is not yet FDA-approved, but is in active clinical trials, and protects decitabine and 5-azacytidine from being rapidly destroyed in the liver and intestines. 

Combining these drugs to treat chemotherapy and immunotherapy-resistant SCLC was successful in preclinical models. Since the drugs the team used are known to be safe for use in humans, clinical trials are feasible.   

“Patients with SCLC and other cancers need modern treatments that are kind, yet effective. By understanding basic mechanisms that cause cancer cells to get stuck in the middle of their journeys to becoming normal non-dividing cells, we can develop kind treatments that remedy or heal toward normality instead of aiming to destroy,” says Dr. Biswas. 

The repurposed drugs, while effective in extending lifespan, did not cure the cancer in preclinical models, reflecting a need to further improve entry of the drugs into SCLC cells. Dr. Saunthararajah’s team is working on modified oral DNMT1-inhibitors that enter and work in the SCLC cells and not just blood cancer cells.  

“Our research demonstrates how treating small cell and other cancers does not need to be a war,” says Dr. Saunthararajah. “By understanding fundamental reasons why cancer cells are cancer cells instead of normal cells, we can fix, repair and heal instead.”