Identification of predictive biomarkers of chemoradiotherapy in lung cancer

Dr. Halmos is working on a way to increase the effectiveness of radiation and chemotherapy that could also lead to personalized non-small cell lung cancer (NSCLC) treatments, especially for the third of all lung cancer patients with locally advanced lung cancer. Research Summary The treatment of locally advanced lung cancer has not changed in the last 30 years with conventional chemotherapy added to chest radiation remaining the standard of care for the 50,000 patients diagnosed each year in the U.S. New research avenues and ideas are sorely needed. Chemotherapy and radiation act on the cancer cells by damaging the DNA; however, the cells have several ways to repair the damage and survive. Our previous studies have shown that reducing two of the ways, ERCC1 and PARP, that DNA is repaired allows the lung cancer cells to be killed more by the chemotherapy, Cisplatin. The goal of our proposed study is to determine if this combination of blocking two DNA repair mechanisms will make chemotherapy and radiation work better together. We will determine if tumors that have low levels of these repair pathways will respond better with combined chemotherapy and radiation. This will help separate out the lung cancer patients who will do well with chemoradiation treatment and potentially reduce the toxicity with treatment. Furthermore, we propose to identify if there are any other pathways in addition which allow the cancer cell to survive in the face of the chemotherapy-radiation treatment. We have preliminarily identified a protein called YAP, which allows the cancer cells to survive despite treatment. Likewise, we would determine if these newly identified pro-survival proteins will help predict which patients might or might not be helped by treatment, and if these proteins allow tumors to become resistant to therapy. Technical Abstract Platinum-based concurrent chemoradiation (CRT) remains the standard treatment for patients with locally advanced, stage III non-small cell lung cancer (NSCLC). Outcomes for this large subgroup remain dismal, and no progress has been made in this area in the last three decades. Novel treatment options and predictive biomarkers to improve upon the outcome and reduce the toxicity of our current treatment paradigms are sorely needed. Our overall hypothesis is that the identification of acquired resistance pathways and synergistic targets for platinum-radiation therapy will lead to improved treatments and patient selection. We will pursue in vitro and in vivo xenograft studies to assess the synergistic role of PARP inhibition and ERCC1 modulation in the setting of CRT and will correlate these findings with a biomarker study using human tumor specimens. We will further validate YAP as a promising actionable target and will assess the interactions of concurrent chemoradiation with YAP blockade based on our preliminary data of synergy. Then, we will pursue an unbiased, functional shRNA genetic screen to identify further essential treatment resistance pathways, and carefully selected targets will be validated through a series of biochemical and functional assessment steps. The predictive value of biomarkers will be tested in retrospective cohorts of patients treated with cisplatin-radiation for locally advanced non-small cell lung cancer enrolled in our lung cancer database. Last, our unique tissue bank of pre- and post-neoadjuvant treatment specimens will be used for the identification of novel resistance markers based on modulation of expression upon neoadjuvant therapy, and functional validation of resistance biomarkers and novel treatment candidates will be pursued. These studies should provide the foundation for biomarker-driven translational and clinical studies in this area of major unmet clinical need.