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D.G. Bebb
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-105 - PARP Inhibition Sensitises ATM Deficient NSCLC Cells to Cisplatin Treatment (ID 3037)
09:30 - 09:30 | Author(s): D.G. Bebb
- Abstract
Background:
We have previously demonstrated that non-small cell lung cancer (NSCLC) cells with low or undetectable ATM are sensitive to synthetic lethality with PARP inhibitor as a single agent. In contrast, lack of ATM alone does not seem to predict sensitivity of these cells to other agents such as cisplatin, a part of standard chemotherapy often used in NSCLC with limited efficacy. Because Cisplatin can induce some DNA damage that can activate ATM, we sought to determine whether PARP inhibition will improve cisplatin efficacy in NSCLC cells that are ATM deficient.
Methods:
A panel of NSCLC cell lines (NCI-H23, NCI-H460, NC1-H522, NCI-H1373) were assessed for ATM status by western blot in terms of a) ATM protein levels and b) ATM functionality by examining active phosphorylated ATM and downstream targets of ATM e.g. p53 and KRAB-associated protein 1 (KAP1) in irradiated cells. The biological effects of PARP-1 inhibition and cisplatin on viability of these cells were examined using the clonogenic survival assay.
Results:
Two NSCLC cell lines H23 and H1373 were found to be ATM deficient and they show increased sensitivity to the combination of cisplatin with PARP inhibition using olaparib, (Table 1). Figure 1
Conclusion:
Here, we show that PARP inhibitor sensitized ATM deficient NSCLC cells to cisplatin. These results suggest that a significant treatment response could be achieved in ATM deficient NSCLC cells with low dose cisplatin and PARP inhibition. We have evidence to suggest that ATM deficiency may be present in as much as 20 - 25% of NSCLC patients. This cohort may be able to benefit from modified therapy using lower dose chemotherapy, producing milder side effects and better quality of life.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-073 - CXCR4 Expression Is Associated with Poor Survival in Early, Resected NSCLC (ID 3081)
09:30 - 09:30 | Author(s): D.G. Bebb
- Abstract
Background:
CXCR4, a G protein coupled chemokine receptor, and its ligand, stromal cell derived factor-1 (SDF-1), play a critical role in organ specific tumor metastasis. In vitro, CXCR4 expression has been shown to correlate with migration, invasion and adhesion in various cancer cell lines including lung, breast and colon, among others. In clinical studies, patients whose tumors exhibit high CXCR4 expression tend to have a poorer clinical outcome. We previously demonstrated that high expression of CXCR4 by quantitative IHC in a cohort of 170 stage IV NSCLC specimens was associated with significantly decreased overall survival, particularly in the female patients. We subsequently investigated whether CXCR4 also conferred a poorer prognosis in our early stage NSCLC patients with resected disease, to validate our previous findings.
Methods:
After ethical approval was obtained, demographic details, clinical variables and outcome data were gathered on patients diagnosed at the Tom Baker Cancer Centre (TBCC) from 2003 to 2006. Formalin-fixed paraffin embedded tumor specimens were obtained from those patients diagnosed with resected stage I, II or III NSCLC and tissue micro arrays (TMAs) were generated. CXCR4 expression in NSCLC cells was analyzed by immunohistochemistry using anti CXCR4 mAb and the HistoRx PM-2000 platform, then correlated with clinical outcome. Statistical analysis was performed using the Kaplan-Meier method, multivariate analysis and a multi-state model to account for the competing risks of disease free and overall survival.
Results:
Of 1502 patients diagnosed with NSCLC at the TBCC in 2003-2006, 166 had resected (pneumonectomy, lobectomy or wedge resection) stage I (63%), II (30.7%) or III (9.6%) disease. 37.3% of the patients received adjuvant treatment (combined chemoradiotherapy or radical radiotherapy alone) after their surgery. 46.4% of the patients were still alive at the time of analysis. The mean CXCR4 AQUA scores were significantly lower for the early stage patients than those obtained for the advanced stage IV patients (1715.90 vs 2512.44 p< 0.0001). High CXCR4 expression was associated with worse overall survival (p = 0.026) but had no significant effect on disease free survival after resection (p = 0.376). Subgroup analysis showed no significant differences between genders in the association between high CXCR4 expression and clinical outcome.
Conclusion:
CXCR4 is expressed in early stage resected NSCLC tumors and appears to increase significantly from stage I-III to stage IV NSCLC. High CXCR4 expression is associated with significantly poorer overall survival in early stage resected patients, validating our previous findings in stage IV NSCLC using the same method. CXCR4 does not seem to be associated with disease free survival in this cohort of patients, nor does there seem to be any association between gender and the effect of CXCR4 on poor outcome unlike that seen in our stage IV NSCLC patients.
