Previously Funded Research

cell lung cancer (SCLC) is the most lethal type of lung cancer with a median

survival of less than 24 months for all patients. Most current therapies,

including the first-line chemotherapeutic regimen of cisplatin and etoposide,

rely on inducing DNA damage and blocking DNA replication to cause cell death;

however, the effectiveness of these treatments is often limited. While most

patients will initially respond to treatment, most will ultimately fail

because the cancer develops treatment resistance. Thus, more effective

treatments are urgently needed. Recent data in the lab suggests that EZH2 is a

critical determinant of cisplatin resistance in SCLC. Importantly, EZH2 is

overexpressed in SCLC and implicated in its progression. The hypothesis that will

be tested is that EZH2 plays a critical role in mediating cisplatin

resistance in SCLC by promoting DNA damage response activities, and

furthermore that EZH2 inhibition will sensitize cisplatin-resistant SCLC

cells and tumors to cisplatin treatment. We propose to determine how EZH2

mediates cisplatin resistance in SCLC and if EZH2 inhibition can be an

effective therapeutic strategy. Completion of this work will define a novel

role for EZH2 in the DNA damage response in mediating cisplatin resistance in

SCLC and elucidate the significance of EZH2 as a novel therapeutic target for

improving the efficacy of treatment for patients with SCLC who develop

treatment resistance. We anticipate that following completion of this work, a

randomized clinical trial investigating the use of EZH2 inhibitors for

patients who have relapsed on cisplatin-based chemotherapy will be initiated,

which will help bring to fruition the use of EZH2 inhibitors as a

paradigm-changing approach for patients with cisplatin-resistant SCLC in the

next few years.