Virtual Library
Start Your Search
L.F. Petersen
Author of
-
+
OA06 - Prognostic & Predictive Biomarkers (ID 452)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:F. Shepherd, Y. Yatabe
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 1
-
+
OA06.03 - Transcriptome Analysis of ATM-Deficient NSCLC (ID 6196)
14:40 - 14:50 | Author(s): L.F. Petersen
- Abstract
- Presentation
Background:
Current targeted therapy options in lung cancer, such as EGFR and ALK inhibitors, are effective, though limited in use by the low percentage of patients that carry targetable mutations for these biomarkers. Targeting a broader biological process like DNA damage response (DDR), as with recent synthetic lethality exploits in BRCA-deficient tumours, may offer a form of precision therapy for a larger number of patients. We have shown that NSCLC cells deficient in the DDR protein ATM, exhibit similar synthetic lethality when treated with a PARP1 inhibitor, and that NSCLC patients lacking detectable ATM have poorer overall survival. In vitro, ATM deficient, or “ATMic” cells show increased sensitivity to chemotherapeutics at much lower levels when given in combination with PARP inhibitor. This data suggests that ATM status may be an important determinant for treatment modalities including low dose radiation or platin therapy, or novel synthetic lethality therapies. Here, we seek to determine the cause of ATM loss in NSCLC patients through targeted sequencing, and thorough transcriptomic and epigenetic analysis.
Methods:
We perform whole-transcriptome analysis on NSCLC patient samples previously characterized as normal or ATMic, to detect differences in intracellular pathway activation in these tumours. Additional analysis using OncoFinder software identifies possible effective therapies based on which signalling pathways are most active in the normal or ATMic patients. We also perform targeted NGS on these samples. To our knowledge, no sequencing of ATM has been performed on samples that have also been characterized through other methods (i.e. quantitative IHC) to be ATM deficient.
Results:
We have generated a substantial body of evidence showing that ATM loss has significant impact on the cell sensitivity to several therapeutic modalites. As such ATMic tumours may be treated more effectively using specific treatment strategies than their ATM competent counterparts. Initial analysis of NSCLC cell lines using the outlined methodologies distinguishes ATM status and identifies different therapeutic agents based on inherent molecular differences. A complete analysis of the transcriptome profiles of ATMic NSCLC patients will be presented and discussed.
Conclusion:
This research helps complete the overall picture of what the therapeutic implications of ATM loss in NSCLC actually are and how ATMic tumours can best be identified in the clinic. Together, these analyses will give us a stronger understanding of the mechanism for ATM loss in NSCLC, as well as allow us to develop an ATMic “signature” for reliably determining ATM status in patients for directing their treatment options.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P1.02-086 - ATM Mutations in Lung Cancer Correlate to Higher Mutation Rates (ID 6339)
14:30 - 14:30 | Author(s): L.F. Petersen
- Abstract
Background:
Ataxia telangiectasia-mutated (ATM) is a critical first responder to DNA damage in the cell, but despite being one of the most mutated genes in lung cancer, no specific mutation hotspots have been linked with disease development. Our own quantitative analysis of ATM protein levels in patient samples suggests that ATM is lost in 20-25% of cases and that this loss correlates with poor overall survival and increased response to adjuvant chemotherapy treatments. We believe that this may be the result of increased genomic instability within the cancer cells caused by a lack of adequate DNA repair. Given that ATM-deficient cancers may have higher genetic instability, and that ATM is so highly mutated in lung cancer, we sought to quantify the relationship between ATM mutations and genomic instability, as measured by total somatic mutations.
Methods:
Using genomic and sequencing data available from the Broad Institute Cancer Cell Line Encyclopedia (CCLE) and the NIH Cancer Genome Atlas (TCGA), we correlated mutations in ATM and other genes involved with the DNA damage response with the total number of mutations annotated in ~900 cancer cell lines and ~500 lung adenocarcinomas.
Results:
We show that in cell lines across all cancer types, and particularly in lung, breast, and esophageal cancers, mutations in ATM correlate with a significantly higher number of total mutations. Only mutations in the direct damage response genes appeared to associate with total mutations, whereas p53 – while more commonly mutated – did not correlate with higher mutations in cell lines or patients. In lung cancer patients, ATM mutations were similarly correlated with high somatic mutations.
Conclusion:
We have identified a potential relationship between ATM mutation and total somatic mutations in cancer cell line and patient tumour genomes, which may be indicative of overall genetic instability. Analysis of the ATM mutations in cell lines and patient samples clearly shows that there are no specific hotspots for mutation in ATM that correlate with increased total mutations. Thus screening for ATM mutations alone may not be sufficient to indicate loss of function or instability. However, this data may prove useful in developing panels of targets to screen as mutation hotspots of instability, and ultimately to help identify patients that may benefit from targeted or modified therapy options based on ATM-deficiency or higher genetic instability.
-
+
P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P3.01-045 - Sex Differences in CXCR4-Dependent Motility of NSCLC Cells (ID 4932)
14:30 - 14:30 | Author(s): L.F. Petersen
- Abstract
Background:
The overwhelming majority of deaths due to lung cancer result from metastatic progression of the disease. Cytokines, a group of proteins involved in cell signaling, play an important role in activating the migratory and invasive capabilities of cancer cells, and studies have implicated the stromal-derived factor 1 (SDF-1/CXCL12)-CXCR4 cytokine signaling axis in the progression of several metastatic cancers, including that of the lung. Our previous investigations have shown that survival outcomes of female stage IV non-small cell lung cancer (NSCLC) patients with high CXCR4 levels are significantly worse compared to those of patients with low CXCR4, whereas male patients show no difference in survival. Studies in NSCLC cell lines have observed a link between CXCR4/SDF-1 and estrogen receptor (ER) function, as well as proliferation in response to treatment with estradiol (an estrogen) specifically in female cell lines. These previous results form the rationale for this project, which explores potential sex differences in the motility of NSCLC cell lines in response to cytokine and estrogen stimulation.
Methods:
Western blotting and PCR methodologies were used to assess the downstream activation of CXCR4 and estrogen receptor signaling as a means to confirm their activity in the cell lines studied. The migratory potential of NSCLC cells was measured using wound healing migration assays (scratch tests). Cells were incubated in phenol red-free RPMI 1640 media with or without the reagents of interest (SDF-1, beta-estradiol, estrogen and CXCR4 antagonists, among others) and the migration of cells into the wound was quantified to approximate the metastatic behavior of NSCLC cells in the presence or absence of the aforementioned stimuli.
Results:
All NSCLC cells studied showed high levels of CXCR4, but ER expression varied within our cell line panel, largely by gender of origin. Our preliminary data show a tentative but observable difference in how male and female NSCLC cells respond to both stimulation and inhibition of the CXCR4 axis. In addition, estrogen and SDF-1 co-stimulation induces a greater increase in cell motility of female NSCLC cells.
Conclusion:
The results observed may suggest a possible mechanism, through interactions between CXCR4 and estrogen receptor signalling pathways, to explain the extreme survival differences between male and female stage IV NSCLC patients with high CXCR4 expression.
