Non-small cell lung cancer (NSCLC)

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.