Alexander Lazar

Publications (173) View all

• Article: Frequency and Spectrum of BRAF Mutations in a Retrospective, Single-Institution Study of 1112 Cases of Melanoma.

  Wesley O Greaves, Shalini Verma, Keyur P Patel, Michael A Davies, Bedia A Barkoh, John M Galbincea, Hui Yao, Alexander Lazar, Kenneth D Aldape, L Jeffrey Medeiros, Rajyalakshmi Luthra
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  ABSTRACT: The US Food and Drug Administration (FDA) approved vemurafenib to treat patients with metastatic melanoma harboring the BRAF c.1799T>A (p.V600E) mutation. However, a subset of melanomas harbor non-p.V600E BRAF mutations, and these data are of potential importance regarding the efficacy of current targeted therapies. To better understand the BRAF mutation profile in melanomas, we retrospectively analyzed data from 1112 primary and metastatic melanomas at our institution. The cohort included nonacral cutaneous (n = 774), acral (n = 111), mucosal (n = 26), uveal (n = 23), leptomeningeal (n = 1), and metastatic melanomas of unknown primary site (n = 177). BRAF mutation hotspot regions in exons 11 and 15 were analyzed by pyrosequencing or with the primer extension MassARRAY system. A total of 499 (44.9%) specimens exhibited BRAF mutations, involving exon 15 [497 (99.6%)] or exon 11 [2 (0.4%)]. p.V600E was detected in 376 (75.4%) cases; the remaining 123 (24.6%) cases exhibited non-p.V600E mutations, of which p.V600K was most frequent [86 (17.2%)]. BRAF mutations were more frequent in nonacral cutaneous [398 (50.1%)] than acral melanomas [18 (16.2%)] (P < 0.001); however, there was no significant difference among cutaneous histological subtypes. All mucosal, uveal, and leptomeningeal melanomas were BRAF wild type (WT). The high frequency of non-p.V600E BRAF mutations in melanoma has important implications, because the FDA-approved companion diagnostic test for p.V600E variably detects some non-p.V600E mutations, but the therapeutic efficacy of vemurafenib is not well established for such mixed-mutation lesions.
  The Journal of molecular diagnostics: JMD 12/2012; · 3.48 Impact Factor
• Article: RNA Interference of PARG Could Inhibit the Metastatic Potency of Colon Carcinoma Cells via PI3-Kinase/Akt Pathwa

  Qiaozhuan Li, Ming Li, Wang Ya-Lan, Fauzee Nilufer Jasmine Selimah, Pan Juan, Yang Yi, Yang Lian, Alexander Lazar
  Cellular Physiology and Biochemistry 04/2012; 29(3-4):361-372. · 2.86 Impact Factor
• Article: RNA interference of PARG could inhibit the metastatic potency of colon carcinoma cells via PI3-kinase/Akt pathway.

  Qiaozhuan Li, Ming Li, Ya-Lan Wang, Nilufer Jasmine Selimah Fauzee, Yi Yang, Juan Pan, Lian Yang, Alexander Lazar
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  ABSTRACT: To investigate the role and mechanism of PARG inhibition of metastatic behavior in colonic carcinoma cells. We examined the effects of PARG protein knockdown by RNA interference on invasion, migration and matrix adhesion of colon carcinoma cell lines in vitro and using a murine in vivo model of liver metastasis. Metastasis related genes were detected using mRNA and protein levels. Moreover, LY294002, an Akt phosphorylation inhibitor, was used to determine whether the suppression of metastatic behavior of colon carcinoma cells was mediated by Akt phosphorylation that was confirmed by EMSA. Pyrrolidine dithiocarbamate (PDTC) was used as a selective NFκ-B inhibitor to clarify the relationship between PARG, PARP and NF-κB. PARG protein was undetectable following specific shRNA transfection; mRNA and protein levels of PARP were significantly decreased. PARG-shRNA cells showed high levels of phosphorylated Akt with decreased expression of NF-κB (both total & nuclear), MMP2 and MMP9. However, no additional changes were noted following inhibition of PI3K/Akt pathway by LY294002 in the PARG-shRNA cells; these cells displayed reduced number of liver metastases when characterized in the murine in vivo model. PARG knockdown, concomitant with inhibition of PARP, suppressed the metastatic potency of colon carcinoma cells by activation of PI3K/Akt signaling pathway.
  Cellular Physiology and Biochemistry 01/2012; 29(3-4):361-72. · 2.86 Impact Factor
• Article: ROR2 is a novel prognostic biomarker and a potential therapeutic target in leiomyosarcoma and gastrointestinal stromal tumour.

  Badreddin Edris, Iñigo Espinosa, Thomas Mühlenberg, Amanda Mikels, Cheng-Han Lee, Sonja E Steigen, Shirley Zhu, Kelli D Montgomery, Alexander J F Lazar, Dina Lev, Jonathan A Fletcher, Andrew H Beck, Robert B West, Roel Nusse, Matt van de Rijn
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  ABSTRACT: Soft-tissue sarcomas are a group of malignant tumours whose clinical management is complicated by morphological heterogeneity, inadequate molecular markers and limited therapeutic options. Receptor tyrosine kinases (RTKs) have been shown to play important roles in cancer, both as therapeutic targets and as prognostic biomarkers. An initial screen of gene expression data for 48 RTKs in 148 sarcomas showed that ROR2 was expressed in a subset of leiomyosarcoma (LMS), gastrointestinal stromal tumour (GIST) and desmoid-type fibromatosis (DTF). This was further confirmed by immunohistochemistry (IHC) on 573 tissue samples from 59 sarcoma tumour types. Here we provide evidence that ROR2 expression plays a role in the invasive abilities of LMS and GIST cells in vitro. We also show that knockdown of ROR2 significantly reduces tumour mass in vivo using a xenotransplantation model of LMS. Lastly, we show that ROR2 expression, as measured by IHC, predicts poor clinical outcome in patients with LMS and GIST, although it was not independent of other clinico-pathological features in a multivariate analysis, and that ROR2 expression is maintained between primary tumours and their metastases. Together, these results show that ROR2 is a useful prognostic indicator in the clinical management of these soft-tissue sarcomas and may represent a novel therapeutic target.
  The Journal of Pathology 01/2012; 227(2):223-33. · 6.32 Impact Factor
• Article: Combining EGFR and mTOR blockade for the treatment of epithelioid sarcoma.

  Xianbiao Xie, Markus P H Ghadimi, Eric D Young, Roman Belousov, Quan-Sheng Zhu, Juehui Liu, Gonzalo Lopez, Chiara Colombo, Tingsheng Peng, David Reynoso, Jason L Hornick, Alexander J Lazar, Dina Lev
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  ABSTRACT: Molecular deregulations underlying epithelioid sarcoma (ES) progression are poorly understood yet critically needed to develop new therapies. Epidermal growth factor receptor (EGFR) is overexpressed in ES; using preclinical models, we examined the ES EGFR role and assessed anti-ES EGFR blockade effects, alone and with mTOR inhibition. EGFR and mTOR expression/activation was examined via tissue microarray (n = 27 human ES specimens; immunohistochemistry) and in human ES cell lines (Western blot and quantitative reverse transcriptase PCR). Cell proliferation, survival, migration, and invasion effects of EGFR and mTOR activation treated with erlotinib (anti-EGFR small-molecule inhibitor) alone and combined with rapamycin were assessed in cell culture assays. In vivo growth effects of erlotinib alone or with rapamycin were evaluated using severe combined immunodeficient mouse ES xenograft models. EGFR was expressed and activated in ES specimens and cell lines. EGFR activation increased ES cell proliferation, motility, and invasion and induced cyclin D1, matrix metalloproteinase (MMP) 2, and MMP9 expression. EGFR blockade inhibited these processes and caused significant cytostatic ES growth inhibition in vivo. mTOR pathway activation at varying levels was identified in all tissue microarray-evaluable ES tissues; 88% of samples had no or reduced PTEN expression. Similarly, both ES cell lines showed enhanced mTOR activity; VAESBJ cells exhibited constitutive mTOR activation uncoupled from EGFR signaling. Most importantly, combined erlotinib/rapamycin resulted in synergistic anti-ES effects in vitro and induced superior tumor growth inhibition in vivo versus single agent administration. EGFR and mTOR signaling pathways are deregulated in ES. Preclinical ES model-derived insights suggest that combined inhibition of these targets might be beneficial, supporting evaluations in clinical trials.
  Clinical Cancer Research 08/2011; 17(18):5901-12. · 7.74 Impact Factor