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H. Lemjabbar-Alaoui
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MINI 23 - Lung Cancer Risk: Genetic Susceptibility and Airway Biology (ID 135)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:P.E. Postmus, R. Young
- Coordinates: 9/08/2015, 16:45 - 18:15, 401-404
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MINI23.13 - Extracellular Sulfatase SULF2: A Potential Biomarker for the Early Detection of Lung Cancer (ID 3079)
17:55 - 18:00 | Author(s): H. Lemjabbar-Alaoui
- Abstract
- Presentation
Background:
The extracellular sulfatases (SULF1 and SULF2) are overexpressed in a wide assortment of human cancers. SULF2, in particular, has been shown to drive carcinogenesis in non-small cell lung cancer (NSCLC), malignant astrocytoma, and hepatocellular carcinoma. As extracellular enzymes that are both tethered to the cell membrane and secreted, the SULFs and their heparan sulfate proteoglycan (HSPG) substrates are present in the extracellular environment. We hypothesize that the blood levels of SULF2 can serve as biomarkers for the early detection of NSCLC and malignant astrocytoma. The primary goal of this study is to evaluate the patient tumor and blood samples for the presence of the SULF2 in order to develop novel biomarkers for the early detection of NSCLC.
Methods:
We identified patients who underwent lung resection for adenocarcinoma (ADC) (41 patients) or squamous cell carcinoma (SCC) (51 patients) at our institution from 2000 to 2006. We excluded patients with recurrent lung cancer, or less than 3 mm of invasive tumor on H&E slide. A section from each paraffin-embedded tissue specimen was stained with a monoclonal antibody to SULF2. A pathologist determined the percentage (0-100%) and intensity (0-3) of tumor cells staining. Survival analysis was performed using a multivariate Cox proportional hazards model. We developed an ELISA to detect SULF2 in human blood. After testing a number of different strategies including using different combinations of our anti-SULF2 mAbs, we determined that a sandwich ELISA with capture mAb 5C12 followed by detection with biotinylated mAb 8G1 was best for the most sensitive detection of SULF2.
Results:
SULF2 staining (either tumor or stroma) was positive for 82% of the samples The SCC samples had a higher mean percentage of tumor staining compared to the ADC samples (100% vs. 60%; p<0.0005). However, after adjusting for age, sex, race, histologic type, stage, and neoadjuvant therapy, there was no significant association between percentage of SULF2 tumor staining and overall survival. Nonetheless, these initial findings are very encouraging, because the vast majority of ADC samples, including early stage disease, and all of the SCC tumor samples have some degree of staining for SULF2 protein. Using our SULF2 ELISA assay, we analyzed plasma samples from 54 healthy donors and 85 patients with newly diagnosed early stage NSCLC before surgical resection. The level of SULF2 protein is significantly higher in patients with NSCLC compared with healthy controls (738.4 ± 55.17, vs. 439.4 ± 40.88 pg/mL; p<0.0001).
Conclusion:
SULF2 protein was detected in the vast majority of tumor and blood samples of patients with lung cancer. Although additional studies are required, these data provide the first indication that SULF2 blood level may be a useful biomarker for the early detection of lung cancer.
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-016 - Ponatinib Shows Promise in Malignant Pleural Mesothelioma Cells with Abl Pathway Dysregulation (ID 723)
09:30 - 09:30 | Author(s): H. Lemjabbar-Alaoui
- Abstract
Background:
Malignant pleural mesothelioma (MPM) remains a lethal cancer with limited treatment options. Various tyrosine kinases including c-Abl/Arg, FGFR1, Src and PDGFRa/b have been implicated in driving the growth of MPM. Ponatinib is an FDA approved potent multi-target inhibitor of cAbl/Arg, PDGFRα, VEGFR2, FGFR1, and Src. The aim of this study was to investigate the effects of ponatinib on MPM cells.
Methods:
The in vitro effect of ponatinib on different MPM cell lines (H2052, MSTO211H, H2452, H28) were evaluated by MTS assay and the effect on cell migration was determined using a “scratch wound” assay. Levels of phosphorylated-Crkl (pCrkl) were evaluated by western blot and double-strand DNA breaks (DSDBs) measured via the surrogate marker γ-H2AX in an ELISA assay. A xenograft MPM model was used to examine the effects of ponatinib on tumor grown in vivo.
Results:
High levels of pCrkl were expressed in all MPM cell lines studied indicating c-Abl/Arg pathway activation. In vitro, ponatinib was effective against all MPM cell lines by cytotoxicity assay, led to dramatic cell migration inhibition, significantly reduced pCrkl expression, and increased DSDBs. In vivo, ponatinib blunted tumor growth in a xenograft model. Reduced pCrkl levels were observed in xenograft tumor specimens following ponatinib treatment.
Conclusion:
Inhibition of Abl kinase activity with ponatinib is a potential therapeutic approach in MPM patients with Abl pathway dysregulation. pCrkl shows promise as a biomarker of increased Abl kinase activity and may be useful in identifying MPM patients most likely to benefit from ponatinib.
