Adenocarcinoma

Improvements in outcomes for cervix cancer and bowel cancer provide support for the concept that early diagnosis has the greatest promise to improve cancer outcomes. Unfortunately our improved understanding of the molecular basis of lung cancer has not translated into effective means for early detection. There is at the present time a substantial need for simple but accurate non-invasive tests to detect lung cancer before it is advanced to the point that treatment is rendered ineffective. Blood based biomarker tests provide an ideal approach given that asymptomatic subjects have blood drawn at the time of routine check-ups. The public health impact of the development of effective blood based tests for the detection of lung cancer are quite substantial, given the millions of subjects who are at risk for lung cancer due to current smoking or due to a past history of smoking. Additionally there is a need to develop tests to identify subjects at risk for developing lung cancer who are never-smokers given that never smokers with lung cancer represent some 15% of cases and lung cancer among never smokers is number 7 on the top ten list of cancer killers. This two-year program of research builds on the identification of candidate markers for lung cancer by a team of three PI’s at the Fred Hutchinson Cancer Research Center with expertise in Thoracic Oncology, Cancer Epidemiology and Prevention, and Molecular Diagnostics. Our goals are to develop blood tests to 1- identify never smoker subjects at increased risk of developing lung cancer (C. Li, PI); 2- detect lung cancer before onset of symptoms (G. Goodman, PI); and 3- distinguish between benign and malignant lesions identified by CT scans (S. Hanash, PI). If successful this research program will result in a paradigm shift in our approach to lung cancer screening.

Folate is a B vitamin that is very important for maintaining health and for protecting against a range of major diseases. It is obtained as ‘natural’ folate from food, in particular leafy green vegetables, or as the synthetic form folic acid from supplements and products made with fortified flour. There are genetic differences in the enzymes that control the way that folate is used inside cells; folate is actually present as multiple forms that support different biochemical processes, and these differences confer different levels of susceptibility to diseases that are associated with low folate and altered folate metabolism. Some of the genetic differences have been linked to lung cancer, and some have recently been linked to good responses to pemetrexed, an anti-folate drug that is used to treat lung cancer. The goal of this project is to define the main folate-related genetic variants AND the relative amounts of the different forms of folate inside cells in patients with lung cancer, and to establish whether any of these factors are over-represented in (i) lung cancer patients compared to healthy individuals, and, even more importantly, in (ii) lung cancer patients who show superior responses to pemetrexed. The project has the potential to identify genetic markers and/or biomarkers that could be used to guide lung cancer chemotherapy.

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.

There is recent evidence that metformin, a drug commonly used to treat diabetes, has anticancer effects and can significantly improve responses of breast cancers to chemotherapy without added toxicity. We propose to review clinical records of lung cancer patients treated over the past 25 years at Johns Hopkins to determine whether metformin treatment is associated with improved response to chemotherapy for lung cancer. Because our preliminary laboratory work suggests that lung cancer cells with mutations of the LKB1 gene are particularly sensitive to metformin, we will secondarily determine whether mutations of the LKB1 gene (which is mutated in up to 40% of lung adenocarcinomas) are associated with a higher frequency of response to chemotherapy among these patients treated with metformin. Finally, we will conduct studies in the laboratory to further examine the possible link between LKB1 mutations and response to chemotherapy in combination with metformin. Establishing such a link could lead to improved chemotherapy (using metformin in combination with conventional chemotherapy drugs) and to development of a biomarker that can identify patients with cancers that might be particularly responsive to metformin in combination with conventional chemotherapy.

Even with all of the targeted therapies being developed today, lung cancer is only curable when diagnosed early enough for surgical resection, or combined chemotherapy and thoracic radiation. The recent finding that screening CTs to identify early stage lung cancers can reduce mortality also refocuses our efforts on improving the definitive therapy of localized disease. In most studies, however, cure rates for stage I or II lung cancers are between 50 and 70%, and chemotherapy after surgery improves this only a few percent, and chemotherapy is toxic in almost all patients. The point of these studies is to increase the number of cures achieved in patients with early stage lung cancer and minimize the side-effects of therapy by attacking 3 goals: 1) identifying which tumors are likely to relapse and thus might benefit from additional therapy, 2) identifying which patients will benefit from the addition of chemotherapy after surgery, and 3) figuring out which signals in tumors are associated with those that will relapse to define new types of treatment targeted at these signals. We will take the novel approach of using both state-of-the-art evaluation of both proteins and genes in the same cells to define these groups.

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.