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Y.C. Tan
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MINI 21 - Novel Targets (ID 133)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:B.P. Levy, D.S. Tan
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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MINI21.06 - Role of the Focal Adhesion Protein Paxillin in Lung Cancer - From Genetic Alterations to Novel Mitochondrial Functionality (ID 2188)
17:15 - 17:20 | Author(s): Y.C. Tan
- Abstract
- Presentation
Background:
Cytoskeletal and focal adhesion abnormalities are observed in several types of cancer including lung cancer, which is attributed to a greater number of deaths than prostate, breast and colorectal cancers combined. Paxillin is a 68 kDa protein that is an integral part of the focal adhesion and acts as an adaptor molecule. We initially cloned the gene for paxillin, and localized it to chromosome 12q24. We have previously reported that paxillin can be mutated (approximately 8%), amplified (5-7%), and/or overexpressed in almost 80% of lung cancer patient samples. Paxillin protein is upregulated in more advanced stages of lung cancer compared with earlier stages and is a prognostic factor for non-small cell lung cancer (NSCLC). Paxillin gene is amplified in some pre-neoplastic lung lesions as well as neoplastic lesions. We identified 22 different variants of paxillin mutation in our initial investigation especially between the LD and the LIM domains (Jagadeeswaran et al. 2008). There are mutations that have been validated in the TCGA set. We selected six mutants to perform further studies ((P52L, A127T, P233L, T255I, D399N, and P487L as well as wild-type as control). Our investigations focused on an effort to understand the contribution of molecular abnormalities found in paxillin and their relationship to mitochondrial functionality.
Methods:
HEK293 cells as well as a paxillin null NSCLC cell line H522 was used to overexpress the above paxillin mutants and wild-type paxillin. Live cell confocal microscopy was performed to evaluate cell motility, immunoprecipitation to determine interaction with other proteins, and gene expression analysis was performed to evaluate effects on gene expression.
Results:
Among the mutations we investigated, we found that the most common paxillin mutant A127T in lung cancer cells enhanced cell proliferation, focal adhesion formation and co-localized with the anti-apoptotic protein B cell CLL/Lymphoma 2 (BCL-2), which among other sites also localizes to the mitochondria. We further found that when these variant clones of activating mutations were expressed in HEK293 cells, they conferred phenotypic changes resembling neoplastic cells. In gene chip microarrays assay investigating gene expression modulation conferred by these mutations in these same HEK293 cells, we found that P52L, A127T, T255I, P233L and D399N mutations, compared to wild-type paxillin, indeed modulated the expression of a significant number of genes. In particular, there were a number of mitochondrial signature proteins that were altered in the various mutants. Analyzing mitochondrial functions by measuring the interaction of these mutants with mitochondrial proteins MFN2, and DRP1, we identified that they alter mitochondrial dynamics, with significant fission rather than fusion. Paxillin also translocated from the focal adhesion to the mitochondrial membrane. In relationship to cisplatin responsiveness, PXN and mutant overexpression lead to cisplatin resistance.
Conclusion:
These data suggest that wild-type and mutant paxillin variants play a prominent role in neoplastic changes with direct implications in lung cancer progression and hence, its potential as a therapeutic target needs to be explored further.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-061 - The Chicago Thoracic Oncology Database Consortium: A Multi-Site Database Initiative (ID 946)
09:30 - 09:30 | Author(s): Y.C. Tan
- Abstract
Background:
An increasing amount of clinical data is available to biomedical researchers, but specifically designed databases and informatics infrastructures are needed to handle this data effectively. Multiple research groups should be able to pool and share this data in an efficient manner. The Chicago Thoracic Oncology Database Consortium (CTODC) was created to standardize data collection and facilitate the pooling and sharing of data at institutions throughout Chicago and across the world.
Methods:
The Salgia Laboratory has implemented the Thoracic Oncology Program Database Project (TOPDP) Microsoft Access, the TORP Velos, and the TORP REDCap databases for translational research efforts. Standard operating procedures (SOPs) were created that document the construction and proper utilization of these databases. These SOPs have been made available freely to other institutions that have implemented their own databases patterned on these SOPs. In order to evaluate the effectiveness of this consortium, we have performed an investigation examining patients receiving erlotinib at three institutions belonging to the CTODC: The University of Chicago Medical Center, Ingalls Health System, and NorthShore University Health System.
Results:
A cohort of 373 lung cancer patients who are taking erlotinib was identified by querying data from all three institutions of the consortium. The patients’ demographic and clinical data were compiled. In addition, the EGFR statuses of patients were analyzed, showing that out of the 70 patients that were tested, 55 had mutations while 15 did not have any mutations. The overall survival and duration of treatment were calculated from the data that was provided. It was shown that patients with an EGFR mutation had longer duration of erlotinib treatment and longer overall survival compared to patients who received erlotinib and were EGFR wild type.
Conclusion:
The investigation described herein demonstrates the successful data collection from multiple institutions in the context of a collaborative effort. However, the investigation identified many challenges in this type of collaboration, such as difficulty of transferring data between institutions and potential duplication of patient data. Overall, these issues do not lessen the findings of the investigation or the effectiveness of the CTODC. With greater cooperation and communication between institutions of the consortium, these issues can be readily resolved. The data presented here can be utilized as the basis for further collaborative efforts and/or development of a larger, more streamlined collection of databases within the consortium.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-037 - Genomic Alterations of KRAS, EGFR, and ALK in Patients with Non-Small Cell Lung Cancer, Single Institution Experience (ID 1722)
09:30 - 09:30 | Author(s): Y.C. Tan
- Abstract
Background:
This study reviews the results of extensive genetic analysis in non-small cell lung cancer (NSCLC) patients from a University of Chicago database in order to: describe how actionable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially actionable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. This study reviews the results of extensive genetic analysis in non-small cell lung cancer (NSCLC) patients from a University of Chicago database in order to: describe how actionable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially actionable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS.
Methods:
Thoracic Oncology Research Program (TORP) Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. Three hundred and sixty four patients included in this analysis had advanced NSCLC and underwent genotype testing by FoundationOne, Caris Molecular Intelligence, and Response Genetics.
Results:
99.4% (159/160) of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor types. However, mutations were not mutually exclusive. For the entire cohort 28% of patients were African Americans; adenocarcinoma was the most commonly tested tumor subtype; 91% of KRAS mutations were detected in smokers; 46% of EGFR alterations and 50% of ALK translocations were detected in never smokers. The majority of ALK translocations were detected in adenocarcinomas.
Conclusion:
Personalized medicine is a significant step forward in the realm of lung cancer treatment. In conjunction with NGS to identify and characterize tumor specific molecular abnormalities, biomarker-driven therapies have improved patients’ overall survival. NGS in this study identified potentially actionable genetic alterations across various tumor histology subtypes, races and smoking status. NGS also provided additional information by uncovering targetable concurrent alterations or alterations of unknown significance at this point in time, but potentially targetable in the future.
