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K. Gately
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-066 - PD-L1 Tumor Expression and Its Effect on Overall Survival among Patients with Resected Non-Small Cell Lung Cancer (NSCLC) (ID 6110)
14:30 - 14:30 | Author(s): K. Gately
- Abstract
Background:
Anti-PD1 monoclonal antibodies have demonstrated survival advantage over conventional chemotherapy in progressive metastatic non-small cell lung cancer (NSCLC). The prognostic role of tumoral expression of PD-L1 in NSCLC remains conflicting. We performed this study to evaluate the impact of PD-L1 expression as a prognostic marker in non-metastatic NSCLC.
Methods:
NSCLC patients (pts) who underwent curative resection between 1998 and 2006 in St. James’s Hospital, Dublin were included. PD-L1 status was assessed using Ventana SP124 antibody on archival FFPE surgical tumor specimens, arrayed on tissue microarrays (TMAs) with triplicate 0.6 mm cores. PD-L1 was scored as positive if membranous staining was present in >1% of tumor cells aggregated across the replicate cores to address heterogeneity. Clinical characteristics of the pts were obtained from the hospital electronic database including age, gender, histological subtype, smoking status, grade, tumor size, nodal status, stage and survival data.
Results:
One-hundred and forty-seven patients from our institutional database were included, of which 92 (63.0%) were males, with a median age of 65 years (range: 42-82). 53.1% (n=78) with squamous histological subtype, 43.5% (n=60) were ex-smoker and 50.3% (n=74) had Stage I disease. PD-L1 positivity vs negativity among non-smoker, ex-smoker and current smoker were 13.0% vs 20.9%, 47.8% vs 43.3% and 39.1% vs 35.8% respectively, (p=0.708). PD-L1 expression by IHC was significantly higher in squamous NSCLC compared to non-squamous NSCLC (34.7% vs 14.6%, p=0.030). We also noted increased PD-L1 positivity with rising tumor T stage (T1 vs T2 vs T3 vs T4: 7.1% vs 30.6% vs 0% vs 60%, p=0.023) and grade of differentiation (G1 vs G2 vs G3: 11.1% vs 19.6% vs 44%, p=0.039). There was no correlation between nodal status and PD-L1 expression (N0 vs N1 vs N2: 25.5% vs 25% vs 26.3%, p=0.995). PD-L1 expression appears to be independent of overall disease stage (I vs II vs III: 27.3% vs 22.7% vs 25.0%, p=0.921). The median overall survival for PD-L1 positive vs negative pts was 22.1 vs 20.8 months with HR of 0.64 (95% CI: 0.34-1.12, p=0.123). Overall survival rates of pts with PD-L1 positive vs negative tumors at 2 years were 47.8% vs 44.8% and at 5 years were 43.5% vs 26.9%.
Conclusion:
In our cohort, PD-L1 expression was not associated with poorer survival among resected NSCLC pts. Tumour size and grade of differentiation appear to correlate with PD-L1 expression which warrants further validation in future studies.
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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)
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P3.01-064 - The Overexpression and Cleavage of SASH1 by Caspase-3 Stimulates Cell Death in Lung Cancer Cells (ID 5811)
14:30 - 14:30 | Author(s): K. Gately
- Abstract
Background:
SASH1 (SAM and SH3 domain-containing protein 1) is a recently identified gene with tumour suppressor properties and has a role in induction of apoptosis. Previous work has shown that 90 % of lung cancer cell lines have a decrease in SASH1 mRNA levels (Zeller et al., 2003), however little characterisation of SASH1 function in lung cancer has been undertaken.
Methods:
We evaluated SASH1 expression in transformed normal and malignant non-small cell lung cancer cell lines. We also utilised cell based assays to study the effects of altered SASH1 levels on cell survival and proliferation. Identification of a novel SASH1 targeting drug was performed through connectivity mapping.
Results:
SASH1 protein expression was down regulated in two of the five lung cancer cell lines compared to immortalized normal bronchial epithelial cells. Prognoscan assessment identified decreased SASH1 mRNA expression reduced patient survival. The depletion of SASH1 in lung cells resulted in a significant increase in cellular proliferation in cancer lung cells. Connectivity mapping predicted the drug Chloropyramine would lead to an increase in SASH1 expression. We demonstrated that Chloropyramine upregulates SASH1 in malignant cell lines. In keeping with this we have demonstrated the Chloropyramine inhibited lung cancer proliferation in vitro. We also explored the role of SASH1 in apoptosis. Following ultraviolet light exposure SASH1 is cleaved by Caspase-3. The C-terminal fragment of SASH1 then translocates from the cytoplasm to the nucleus where it associates with chromatin. The overexpression of wild type SASH1 or cleaved SASH1 amino acids 231-1247 leads to an increase in apoptosis, however loss of the SASH1 cleavage site and/or nuclear translocation prevents this initiation of apoptosis. Mechanistically SASH1 cleavage is required for the translocation of the transcription factor NF-κB to the nucleus. The use of the NF-κB inhibitor DHMEQ demonstrated that the effect of SASH1 on apoptosis was dependent on NF-κB, indicating a co-dependence between SASH1 and NF-κB for this process.
Conclusion:
We have shown that SASH1 contributes to apoptosis via a NF-κB-dependent mechanism. Agents that upregulate SASH1, such as chloropyramine or SASH1 gene therapy, are potential novel approaches to the management of NSCLC in the future.
