Non-small cell lung cancer (NSCLC)

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.

Screening smokers with CT can detect lung cancer at relatively early stages, and thus reduce mortality. However, CT screening for lung cancer has a poor specificity, often resulting in unnecessary treatments to smokers who have benign diseases. The objective of this proposal is to develop genomic- and non-coding RNA (ncRNA)-based biomarkers in sputum that can complement CT for lung cancer early detection in smokers.  Proposed aim 1 is to define sputum ncRNA signatures of early-stage lung cancer using next-generation sequencing (NGS). Proposed aim 2 is to optimize a panel of sputum ncRNA biomarkers with CT for the early detection of lung cancer. Proposed aim 3 is to integrate our previously identified genomic biomarkers and the newly optimized panel of ncRNA biomarkers with CT for the early detection of lung cancer in independent case-control series. Future use of the biomarkers in clinical practice for screening smokers for lung cancer will increase CT’s specificity, and hence reduce harmful and unnecessary treatments to many smokers who have benign diseases. Integrating the biomarkers with CT could assist making decisions for the management of abnormal findings in the lungs and enabling effective treatments to be immediately initiated for lung cancer. The study will translate the strengths of novel ncRNA profiling data developed from NGS into clinical settings by using a simple and cost-effective approach, and thus bridge the gap between basic research and patient care.

A significant fraction of NSCLC have mutant KRAS which predicts poor response to cytotoxic therapy and portends a poor prognosis. Despite the discovery of the first mutation in the KRAS oncogene in NSCLC over two decades ago, there are no current therapies targeting this critical oncogene. In this proposal we explore a novel and exciting therapeutic strategy to target KRAS-mutant NSCLC through the combination of Hsp90 and mTOR inhibition. We have preclinical evidence suggesting that the combination of ganetespib and an mTOR inhibitor may be an effective therapeutic strategy for patients with KRAS- mutant NSCLC. In Aim 1, we will define resistance mechanisms to single-agent ganetespib in KRAS- mutant NSCLC. The identification of resistance mechanisms to single-agent ganetespib will reveal novel pathways that we can then target in combination with an Hsp90 inhibitor. In Aim 2, we will test the hypothesis that activation of the mTOR pathway through alterations in STK11 or PI3KCA mutations will predict response to the combination. Finally, in Aim 3 we will translate our studies to the clinic in a phase I/II trial of the combination of ganetespib and an mTOR inhibitor in patients with advanced KRAS-mutant lung adenocarcinoma. Importantly, we will have correlative studies looking at response in subpopulations of KRAS-mutant tumors that are hyperactive for the mTOR pathway (STK11, PIK3CA mutations). This translational approach will allow us to identify biomarkers that we can use to effectively target this combination to the patients with greatest chance to benefit from this therapy.