Ite A. Laird-Offringa Associate Professor Biochemistry & Molecular Biology, Surgery Keck School of Medicine USC / Norris Comprehensive Cancer Center

Education:
BS 1983 Biology - University of Leiden, Netherlands
MS 1985 Molecular Biology - University of Leiden, Netherlands
PhD 1991 Medical Biochemistry - University of Leiden, Netherlands

Postdoctoral Research Fellowship:
1991 - 1996 Harvard Medical School, Massachusettes

Started at USC: 1996

Research Topics: Lung Cancer, Cancer Genetics, Epigenetics, RNA/DNA-protein interaction, DNA methylation, Immune Response in Cancer

Research Description

Lung Cancer

Our studies of small cell lung cancer stimulated our interest in developing tools for early diagnosis of lung cancer, which is the cancer that kills the most Americans every year. More people die of lung cancer than from breast, prostate, and colon cancer combined. The high death rate is largely a result of the absence of accurate early detection tools. To develop markers for molecular diagnosis of lung cancer, we are taking two approaches. On the one hand, we are analyzing the expression of specific antibodies in the blood of lung cancer patients. We have recently shown that autoantibodies known to arise in a fraction of human SCLC patients also appear in a mouse model of SCLC (manuscript in press) and will be using this mouse model to dissect the mechanism of the SCLC-related immune response. On the other hand, we are studying DNA methylation patterns in lung cancer and other neoplasms found in or near the lung (such as mesothelioma). This work is carried out in collaboration with a multidisciplinary team of investigators inside and outside USC, and in concert with the new USC Epigenome Center.

DNA Methylation

DNA methylation is and ‘epigenetic’ modification of DNA that is reversible. It does not change the DNA sequence, but it can change the level at which genes are expressed and it can be inherited from one cell to the next. In mammals, DNA methylation occurs on cytosines that are followed by guanosines (so-called CpG dinucleotides). The methylation of CpG-rich regions (“CpG islands”) in the promoter regions of genes is associated with gene silencing, and is now known to be a key mechanism for the inactivation of tumor suppressor genes in cancer. CpG island hypermethylation has been seen in many kinds of cancer, and it appears that distinct profiles of methylated genes are present in different types of cancer. Our research is aimed at identifying genes that are specifically methylated in lung cancer and mesothelioma. This information will be applied towards our most urgent goal: the development of tools for early cancer detection, so that the tumor could be removed before it spreads. However, DNA methylation information will also be applicable to 1) the development of tools for accurate diagnosis, through identification of panels of genes that are specifically methylated in different types of thoracic cancer, 2) development of predictors of patient outcome, by correlating methylation profiles to clinicopathological characteristics of patients such as response to therapy and survival, and 3) gaining insight into the molecular pathways altered in lung cancer, with the objective of developing targeted drugs.

RNA/DNA-Protein Interaction Analysis

Another area of research in the Laird-Offringa lab is aimed at analyzing the interaction between proteins and DNA/RNA. Our specialty is analyzing the dynamic interaction between proteins and DNA/RNA in real time, using a surface plasmon resonance-based biosensor (Biacore). We are currently investigating the kinetics of the interaction between the methyl-binding domain and methylated DNA and, in collaboration with several labs, the binding of transcription factors to their DNA targets.

Research Funding

Research in the Laird-Offringa lab is funded by two NIH/NCI grants, and by various grants/donations from private foundations or individuals. We have received support from the Wright Foundation, the Whittier Translational Research Fund, the Mesothelioma Applied Research Foundation, Joan's Legacy, the Thomas G. Labrecque Foundation, the Canary Foundation, the Kazan Foundation, and the Hoag Family Foundation. We also have a number of wonderful donors, such as Wally and Conya Pembroke, Michelle and Paul Zygielbaum, Sharon Binder, Bonnie and Tony Addario and others. We deeply appreciate all their contributions, large and small, as well as those of the patients who participate in our research studies by anonymously donating remnants of clinical samples or blood. Our work would not be possible without such fabulous support.

Collaborations

Most of our projects are interdisciplinary collaborations with faculty inside and outside of USC. In the SCLC immune response project, we collaborate with the lab of Anton Berns in the Netherlands and radiologist Peter Conti at USC, in our epigenetic work we collaborate with statistician Kim Siegmund, surgeon Jeffrey Hagen, clinical oncologist Barbara Gitlitz, Peter Laird and members of his lab and the USC Epigenome Center, and pathologist Michael Koss at USC and Keith Kerr from Aberdeen, Scotland. We are also involved in a large collaboration with members of the Canary Foundation and the Early Detection Research Network at NIH. In our kinetic work we collaborate with Ian Haworth from the School of Pharmacy. We believe that together we can all achieve so much more than alone and greatly enjoy our collaborative efforts.

Manuscripts in press/in preparation

Immune response in lung cancer mouse model mimics human anti-Hu reactivity, Meleeneh Kazarian,Joaquim Calbo,Natalie Proost,Catherine L. Carpenter,Anton Berns,and Ite A. Laird-Offringa, J. Neuroimmunol, accepted for publication

Optimization and validation of a panel of DNA methylation markers for squamous cell lung cancer, Anglim, Paul P., Weisenberger, Daniel J.  Campan, Mihaela, Cernosek, Sarka, Oezcelik, Arzu, Hagen, Jeffrey A., Laird, Peter W., Carpenter, Catherine L., Koss, Michael N., Siegmund, Kimberly D., and Laird-Offringa, Ite A., submitted for publication

DNA methylation changes in atypical adenomatous hyperplasia, bronchioalveolar carcinoma, and lung adenocarcinoma. Suhaida A. Selamat, Janice S. Galler, Amit Joshi, M. Nicky Fyfe, Kimberly D. Siegmund, Keith M. Kerr, Ite A. Laird-Offringa, manuscript in preparation