Overcoming chemoresistance through epigenetic modification in SCLC

Small cell lung cancer (SCLC) is an extremely fast-growing type of lung cancer that is most often related to smoking. Patients diagnosed with SCLC that affects more than one area of the body are usually treated with chemotherapy, which travels throughout the body to treat all sites of the cancer. Most patients, up to 70%-80%, tend to have very good responses to chemotherapy at first. Unfortunately, almost all patients eventually stop responding to chemotherapy. Why these small cell lung cancers ultimately stop responding to chemotherapy is not well understood.

Recently, the Charles Rudin laboratory at Memorial Sloan Kettering Cancer Center has created patient-derived xenografts, or patient-derived animal models, to test why some small cell lung cancers stop responding to chemotherapy over time. Using these animal models, we found that a protein called enhancer of Zeste homolog 2 (EZH2), plays an important role in how SCLC develops resistance to chemotherapy. EZH2 does this by decreasing the levels of Schlafen family member 11 (SLFN11), which encourages cells to die after their DNA is damaged. By blocking EZH2 in combination with chemotherapy using irinotecan in mouse models, resistance to chemotherapy was reversed, and the cancer cells began responding to chemotherapy again.

These findings in mouse models from our laboratory provide good evidence that combining a drug that blocks EZH2 with standard chemotherapy might help chemotherapy work more effectively. To answer this question, we will conduct a clinical trial that only has one group of patients, in which all patients receive the same treatment of a drug that blocks EZH2 and standard chemotherapy using irinotecan. We plan to collect blood samples and obtain repeat biopsies on all patients enrolled in this study for additional testing to learn more about the effects of blocking EZH2 on the cancer’s response to chemotherapy. If this experimental drug that blocks EZH2 is shown to be safe and potentially effective when compared with chemotherapy, it would establish a new treatment regimen that can be used not only in patients with SCLC, but potentially in all cancers that grow in response to EZH2.