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P.P. Massion
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-028 - Dual Role of the Focal Adhesion Kinase in Small-Cell Lung Cancer (ID 5890)
14:30 - 14:30 | Author(s): P.P. Massion
- Abstract
Background:
Small cell-lung cancer (SCLC) is a devastating illness with five-year overall survival as low as 5%. The molecular steps leading to SCLC development and progression are still poorly understood and this has translated into the absence of targeted therapies. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase which regulates integrin and growth factor signaling pathways involved in cell proliferation, survival, migration, and invasion. FAK is overexpressed and/or activated in many cancers, including SCLC. We hypothesized that FAK overexpression/activation in SCLC contributes to its aggressive behavior and that FAK may represent a therapeutic target in SCLC.
Methods:
Two SCLC cell lines growing in suspension (NCI-H82, NCI-H146), and adherent SCLC cell lines (NCI-H196, NCI-H446) were treated with PF-228. NCI-H446 and H82 cells were stably transfected with FAK shRNA and/or FRNK using lentivirus vector. Cell proliferation was evaluated by WST-1 assay; cell cycle by flow cytometry with propidium iodide and bromodeoxyuridine; apoptosis by caspase 3 staining in flow cytometry and by cleaved PARPp85 Western blotting (WB); motility by wound healing assay; and invasion by Boyden chambers. FAK expression/activity was evaluated by WB.
Results:
While PF-228 did not modify total FAK expression, it decreased FAK phosphorylation (Y397). Inhibition of FAK activity by PF-228 decreased cell proliferation, DNA synthesis, induced cell cycle arrest in G2/M phases, and increased apoptosis in dose-dependently. PF-228 also decreased motility in the adherent H196-H446 cells. To confirm the specificity of the antitumoral effects of PF-228, we stably transfected SCLC cells with FAK shRNA and FRNK and then analyzed the phenotypic changes induced by these approaches. Knockdown of total FAK protein by transfection of FAK shRNA inhibited FAK activity, but did not have any effect on cell proliferation, DNA synthesis, and cell cycle. However, reintroduction of FRNK in cells stably transfected with FAK shRNA inhibited cell proliferation and DNA synthesis. Expression of FRNK decreased cell proliferation and DNA synthesis in SCLC cells.
Conclusion:
Inhibition of FAK activity by PF-228 in SCLC cell lines demonstrates that FAK activity is required for cell proliferation, cycle progression, survival, and motility, suggesting that FAK inhibition may represent a suitable therapeutic target for SCLC. Inhibition of FAK by a genomic approach suggests that FAK has a dual role in SCLC biology, namely (i) a pro-tumoral effect related to the kinase domain, which induces downstream signals (ii) an anti-tumoral effect mediated by the non-kinase C-terminal domain (FRNK domain), which keeps inactive other pro-tumoral effectors
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SC18 - Precision Screening for Lung Cancer (ID 342)
- Event: WCLC 2016
- Type: Science Session
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:A. Nicholson, G. Ostoros
- Coordinates: 12/06/2016, 16:00 - 17:30, Lehar 1-2
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SC18.02 - Integrating Lung Cancer Biomarkers into Future Screening Programs (ID 6672)
16:20 - 16:40 | Author(s): P.P. Massion
- Abstract
- Presentation
Abstract:
Low-dose computed tomography for high-risk individuals has for the first time demonstrated unequivocally that early detection save lives. The currently accepted screening strategy comes at the cost of a high rate of false positive findings while still missing a large percentage of the cases. Therefore, there is increasing interest in developing strategies to better estimate the risk of an individual to develop lung cancer, to increase the sensitivity of the screening process, to reduce screening costs and to reduce the numbers of individuals harmed by screening and follow-up interventions. New molecular biomarkers candidates show promise to improve lung cancer outcomes. This review discusses the current state of biomarker research in lung cancer screening with the primary focus on risk assessment. The rationale for developing biomarkers for the early detection of lung cancer is very strong and well established. It stems from the fact that, at the population level, the earlier we detect the disease, the better the outcome and the lower the health care cost. The impetus for biomarker development has grown stronger since the NLST trial demonstrated that early detection via chest CT screening reduced the relative risk for lung cancer death in the high risk individuals. Low dose chest CT in this group alone may save up to 12,000 lives a year, but it represents only about 8 % of individuals dying of this disease every year. Thus, much is to be done to capture these lung cancers that escape chest CT screening as currently recommended despite its high sensitivity and specificity. The reason for limited detection relates to how many at-risk individuals are studied with CT and to how we best define this risk. Detection and careful management of indeterminate pulmonary nodules are integral parts of this effort. Lung cancer screening using chest CT also raises many questions, some of which could be addressed with well poised biomarkers. For example, who is at utmost risk for lung cancer? How do we expand the screening criteria from the NLST without causing more harm than good? Once the CT screening studies are done, how do we approach a non-invasive diagnosis of lung cancer? How do we prevent the overdiagnosis bias? Here we focus on biomarkers that could be used in a risk assessment evaluation for screening programs. We will discuss current molecular biomarkers of risk assessment in those without measurable disease and before a chest CT has been done. Consideration of the use of such biomarkers should trigger a discussion with the patient before ordering it to address the intent of the test and the implications of the possible results. Many biomarkers have been developed over the years to predict tumor development. Let us consider the characteristics of such a biomarker to assess the risk of lung cancer. For screening purposes, given the low prevalence of disease, a strong negative predictive value (NPV) of a test is a very attractive feature. High specificity on the other hand is always desirable so we do not overcall cancers (false positive). Should such a test be positive, it would push individuals into a higher risk group to consider appropriate surveillance. The biomarker could measure a genetic risk (e.g. altered metabolism of carcinogens, DNA repair machinery abnormalities, predisposition to inflammation, or germline mutations) or the influence of the environment on tumor development (exposure to carcinogens or surrogates of risk such as epigenetic changes in the airway epithelium or the prevalence of preinvasive lesions). There has been recent interest in the potential for genetic variants to give insight into the pathogenesis of lung cancer. These variants indicate that there is great heterogeneity in mechanisms of disease development that is modulated by inherited genetic variation. With these come the opportunity to improve models predicting lung cancer risk. A larger question of timeliness of biomarker use in clinical practice will be discussed during the presentation. What are the risk and benefits of precision screening? Are current risk prediction models safe to use or robust to guarantee an advantage over current standard of care? There is a clear need to evaluate the benefit of risk assessment biomarkers with repeated measures over time. The assumption is that as risk increases, molecular moieties should be more readily available (e.g. in the circulation) over time. This may be true for tumor specific antigens and ctDNA, but would not apply to genetic risk. Statistical models could test the ability of different biomarkers to complement each other in a single population, in order to eventually determine those that could be tested prospectively. Given biomarkers' non-specificity and commonality in predicting diseases, modeling multiple markers of the same clinical diagnostic criteria can be used to develop more accurate individual and cumulative risk estimates for specific diseases. We should therefore consider a joint effects approach to determine individual biomarker associations as well as to ascertain the impact of simultaneous increases in multiple biomarker concentrations on the diagnosis of lung cancer. Biomarkers of risk would ideally be tested prospectively in a randomized clinical trial. However, given the relatively low prevalence of this disease, the number needed to screen may be prohibitive; therefore the development of registries is most appropriate. Registries are longitudinal cohort prospective studies where a biomarker is introduced but does not force providers to change their management. The lead time to diagnosis may be sufficient to cause a stage shift and therefore improve outcome. Finally, it is through better understanding of the biology of cancer development and of preinvasive lesions that we will shed further light into the field of biomarker research.
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