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Small cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. New strategies are urgently needed to improve clinical outcomes for SCLC patients. Recently, we identified high expression of the DNA-repair protein poly (ADP-ribose) polymerase 1 (PARP-1) in SCLC cell lines and tumors through a large-scale, proteomic profiling project. In vitro data from our group has shown that PARP inhibitors have single-agent activity in SCLC and potentiate the activity of chemotherapies that work by inducing DNA damage. Based on these results, we are conducting an investigator-initiated, Phase II clinical trial of the oral alkylating agent temozolomide (TMZ) with or without the PARP inhibitor ABT-888 for patients with relapsed SCLC. We hypothesize that PARP1’s action as an E2F1 co-activator contributes to the overexpression of multiple E2F1-regulated DNA repair proteins, resulting in resistance to chemotherapy. Thus, targeting PARP1 will decrease expression of E2F1-regulated DNA repair proteins, as well as directly inhibit PARP-mediated DNA repair, resulting in decreased cell viability and improved clinical outcomes in patients treated with TMZ and the PARP inhibitor. In the studies proposed here, we will test in vitro and in vivo sensitivity of SCLC to ABT-888 and TMZ, alone and in combination, and develop predictive biomarkers of response that will be tested in our Phase II clinical trial. The ultimate goal of this laboratory and clinical research is to develop PARP inhibitors as a novel therapy for SCLC.

Small cell lung cancer (SCLC) exhibits aggressive clinical behavior and poor outcome and response to therapy. Moreover, there are no effective strategies for early detection of SCLC. Therefore, there is an urgent need to identify new strategies and markers for SCLC detection. We recently characterized the molecular airway field cancerization (FC) in non-small cell lung carcinoma (NSCLC) patients and identified airway profiles that varied spatially (n=1165) and with time (n=1395) following surgery. Moreover, we characterized the adjacent airway FC in NSCLC (n=1606 genes), a subset of which (n=299) significantly distinguished airways of smokers with lung cancer from those of healthy smokers and another (n=208) separated airways of different NSCLC subtypes. Although we previously showed that SCLCs and adjacent airways are characterized by higher level of allelic losses compared to those of NSCLC cases, the global airway FC in SCLC and its relevance to detection has not been explored. We hypothesize that the molecular airway FC in SCLC is different compared to that in NSCLC or benign lung disease and comprises biomarkers specific for early detection of SCLC. We will 1) perform global expression profiling of the airway FC and tumors or nodules in patients with SCLC, NSCLC, and benign disease for identification of airway markers specific to SCLC and 2) test identified airway mRNA markers for SCLC detection in bronchial and nasal compartments in patients with suspect lung cancer. We anticipate that our proposal, due to its unique resources and approaches, will identify novel markers for SCLC detection.