Conference name
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Eric Santoni-Rugiu

Analysis of ALK in non-small cell lung cancer

Handout

The anaplastic lymphoma kinase (ALK) gene rearrangement has been recently identified as specific oncogenic driver mutation in a distinct subset (~ 5%) of non-small cell lung cancer (NSCLC) patients. The ALK rearrangement typically consists of a small inversion on chromosome 2p23-21, between ALK gene’s exon 20 and different exons (due to different breakpoints) of the echinoderm microtubule-associated protein-like 4 (EML4) gene. Rare ALK translocation partners other than EML4 may be found in NSCLC. Moreover, cases of atypical translocation with an unknown partner (resulting in loss of centromeric probe, as assessed by FISH) also occur. All these rearrangements result in stabilized, chimeric, constitutively active ALK-fusion proteins with potent oncogenic activity. Most of ALK+ NSCLC patients are non/light-smokers, have adenocarcinoma histology, lack EGFR gene mutations, and are susceptible to effective targeted inhibition by the recently approved ALK-inhibitor crizotinib resulting in dramatic therapeutic response in these patients. Thus, up-front screening of oncological patients with advanced NSCLC is now recommendable not only for EGFR-mutations (that would allow treatment with the EGFR tyrosine-kinase-inhibitors), but also for ALK-fusions, in order to possibly select patients candidate for efficacious treatment with crizotinib.

FISH-testing has initially been considered the gold-standard method for diagnostic screening of ALK-rearrangements in NSCLC specimens and has been used in clinical trials evaluating the efficacy of crizotinib. However, immunohistochemical detection of ALK protein expression in NSCLC has now gained popularity, because of the routine availability and broad experience of departments of pathology with IHC, and its lower cost and labour as compared to other methods for assessing ALK-rearrangements, such as FISH and RT-PCR. Normal adult tissues, including lung tissue, do not express ALK with the exception of neural tissue. Thus, protein expression reveals cases that harbour ALK rearrangements leading to ALK fusion-proteins or gene amplification, responsible for increased expression. In line with that, several reports have demonstrated that ALK-IHC can have sensitivity and specificity comparable to ALK-FISH and is recommendable as complementary method for screening and/or assessing ALK-rearrangements in NSCLC specimens. Consistent with this, our own ALK-screening of advanced NSCLC patients from different Danish hospitals during October 2010-January 2013, has shown optimal concordance between the results of FISH and IHC (17+ cases out of 260 ALK-tested, the largest series among Nordic molecular pathology laboratories so far). These and other aspects of ALK-diagnostics as important predictive tool for improving NSCLC’s treatment will be presented and discussed.
 

CV

Education
2005: Specialist in Pathology & Histopathology, Danish National Board of Health
1994: Doctoral degree: D.M.Sc.
1988: M.D., highest marks cum laude & publication of the thesis, University of Pisa, Italy

Career
2010-pres.: Clin. Assoc. Prof., Institute of Clinical Medicine, Copenhagen University
2008-pres.: Leader of Lab. of Molecular Pathology, Dept. of Pathology, Diagnostic Center, Rigshospitalet, Copenhagen
2008-pres.: Senior Consultant, Dept. of Pathology, Diagnostic Center, Rigshospitalet, Copenhagen (main diagnostic activity: thoracic and mediastinal pathology) 
2007-2010: Leader of Biobank, Dept. of Pathology, Rigshospitalet, Copenhagen
2006-2007: Staff Pathologist, Dept. of Pathology, Rigshospitalet, Copenhagen
2000-2005: Resident in Clinical & Surgical Pathology at different Danish hospitals
1999-2000: Adviser for the Molecular Pathology Unit at the European Institute of Oncology, Milan, Italy.
1998-2000: Assistant Professor, Dept. of Experimental Pathology, Pisa Univ., Italy
1997-2000: Visiting Researcher in the lab. of Cell Cycle & Cancer led by Dr. Jiri Bartek, Danish Cancer Society, Copenhagen (working on cancer cell cycle regulation by the c-Myc and E2F oncogenic transctription factors) 
1993-1997: Postdoctoral Fellow (international fellowship granted by the NIH’s Fogarty International Center) & then Visiting Scientist (position granted by the US Federal Government) in the lab. of Dr. Snorri S. Thorgeirsson, National Cancer Institute, NIH, Bethesda, USA (main project: role of the oncogene c-Myc in human hepatocarcinogenesis)
1990-1994: Doctorate of Research, in Experimental Oncology & Tumor Morphology, University of Pisa, Italy (thesis: phenotype of the multidrug resistance 1b gene), Institute of General Pathology, Pisa Univ., Italy
1990-1992: Resident, Dept. of General, Vascular, & Plastic Surgery, Pisa Univ., Italy
Current research interests: translational cancer research, lung cancer, malignant pleural mesothelioma

Academic activities
Supervision: Supervisor for 7 PhD-students, 3 master students & 4 research assistants
Pregraduate teaching: 2010-pres.: different courses on Pathology to medical students, Univ. of Copenhagen
Postgraduate teaching: 2008-pres.: lectures at courses on Pulmonary Pathology, Molecular Pathology, Interstitial Lung Diseases for residents in Pathology and in Pneumology.
2009-pres.: co-organizer & teacher for the PhD-course on Pathology at the Danish Research School on Molecular Mechanisms of Disease (MoMed), BRIC, Univ. of Copenhagen.
 
Chairmanships & memberships 
2009-2012: Chairman of Danish Molecular Pathology Group (DMPG)
Current Board memberships: Danish Assoc. for Cancer Research; Nordic Advisory Board for ALK in NSCLC; MoMed; 2008-2010: Board, Danish Cancer Biobank.
Current memberships: Amer. Assoc. Cancer Res.; Am. Soc. Invest. Pathol.; Thymus & Mediastinal Pathology Working Group of Eur. Soc. of Pathol. (ESP); Molecular Pathology Group of ESP.; International Mesothelioma Interest Group; Nordic Mesothelioma Group.

Publications
55 in peer-reviewed journals; 5 book chapters, co-author of 2 pathology books.
Numerous invited lectures at international meetings, 6 on ALK-diagnostics in NSCLC in the last 2 yrs.

Reviewer for: Acta Oncol., Am. J. Pathol., APMIS, Cancer, Carcinogenesis, Cell Growth & Diff., Clin. Respir. J., EMBO J., FEBS Lett., Gene, Hepatology, J. Pathol., Life Sciences, Liver, Mol. Diagnosis & Therapy, Oncogene, PNAS.

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