Squamous cell lung cancer

The treatment of lung cancer has been revolutionized by the discovery of specific targeted therapies such as erlotinib or gefitinib for EGFR-mutated lung cancer and crizotinib for ALK-translocated lung cancer. These successes have taught us that lung cancer is not just one disease, but a multitude of different diseases, best defined by the specific tumor genetic changes that are driving tumor growth and that can serve as targets for therapy. At Massachusetts General Hospital, we have been performing tumor genetic testing via SNaPshot, a panel of known oncogenic mutations, since 2009. We have found that approximately 40% of our patients do not have an identifiable mutation. For these patients, identifying what tumor genetic changes are driving their cancer will be critical to develop effective targeted therapy. This proposal therefore is focused on those patients who did not have an identifiable tumor mutation, with the hope that we can discover new targets for effective therapy. We plan to do this by two methods: First, we will perform whole exome sequencing, i.e. sequencing the coding regions of the tumor genome, on the tumors of patients who did not have any identifiable tumor mutations. Second, we will screen for chromosomal rearrangements involving tyrosine kinases. Tyrosine kinases are of particular interest in cancer, as they play a role in cell growth and proliferation, and more importantly are potentially “druggable.” With this two-pronged approach, we hope to identify novel tumor-related genetic changes that will lead to new targeted therapies for lung cancer.

Lung cancer is the leading cause of death for men and women in the United States. Contributing to the lethality of this disease is our inability to detect treatable early stage lung cancer resulting in the majority of lung cancer patients being diagnosed with incurable advanced disease. Computerized tomography (CT) screening has shown promising preliminary results in the detection of early stage lung cancer (with a 20% reduction in lung cancer mortality); however, it remains to be determined how it will be incorporated into standard practice. Biomarker-based screening methods that complement CT – and that are accessible to all current and former smokers – will be vital to making early lung cancer detection more attractive. Our goal at UC Davis is to combine our multidisciplinary leaders in lung cancer practice and research (Drs. Kelly, Gandara, Cooke, Yoneda and Murin) with “omics” experts (Drs. Miyamoto, Fiehn, and Lebrilla), who have developed sensitive technologies to detect and analyze sugars, lipids, and metabolites in human specimens, to identify blood biomarkers for early stage lung cancer that can be used in conjunction with CT screening. We will examine biomarker compositions of tumor tissue, non-malignant tissue, and blood in cancer patients, healthy controls and patients with benign lung nodules, to ultimately identify easily detectible blood markers that: 1) will detect early stage cancer and 2) are sensitive and specific. Such biomarkers will contribute to earlier, more informative lung cancer detection and make tailored lung cancer therapy and increased cure rates possible.

Lung cancer is the leading cause of cancer death in the world and has a dismal 16% 5 year survival rate. One reason for this discouraging statistic is that until recently, no early detection test had been validated. The National Lung Screening Trial (NLST) has recently demonstrated that CT screening results in a 20.3% decrease in lung cancer mortality compared to chest radiograph screening. It is now clear that CT scans will be increasingly used for lung cancer screening.

CT scans detect lung nodules in 20-50% of patients, while only 1-2% have lung cancer. Thus, CT scanning has low specificity (many false positive tests) for lung cancer. Patients and physicians are often put in the situation of having to decide between serial CT scans to look for nodule enlargement (which takes months) or an immediate biopsy strategy. Each approach has potential drawbacks: serial observation can result in delay in diagnosis and an immediate biopsy strategy can lead to unnecessary morbidity and expense. Biomarker based testing to determine risk for lung cancer is not currently available, but would be invaluable in aiding clinical decision making in this setting.

We propose to further refine and validate two promising risk biomarkers, abnormal chromosome numbers in sputum cells and a blood test assessing multiple bioactive proteins as guides to clinical decision making for patients and physicians confronted with indeterminate lung nodules and compare their performance to prediction models based on nodule and patient characteristics.