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Awardee Spolight

2005 NREF Research Fellow Daniel P. Cahill, MD, PhD Massachusetts General Hospital Sponsor: David N. Louis, MD Project Title: Analysis of oligodendroglioma gene expression profiles

"The NREF Research Fellowship has provided the unique opportunity to pursue my interest in the molecular genetics of brain tumors. Hopefully, these studies will provide insight into the genes underlying brain tumor formation."   - Daniel P. Cahill, MD, PhD

Daniel P. Cahill  MD, PhD

Dr. Cahill’s proposal focuses on the analysis of gene expression profiles of malignant gliomas, with an aim to identify the pathways involved in these brain tumors. Previous studies in Dr. Louis’ lab group have characterized the gene expression profiles of approximately 12000 genes in 90 tumors, resulting in a molecular system for identification of tumor type and prediction of clinical outcome. Dr. Cahill is now pursuing detailed analyses of large-scale datasets to identify glioma subtype-specific genes. Study of these genes will provide insight into the molecular genetic basis of glioma growth and chemosensitivity, ultimately resulting in the identification of specific targets for therapeutic intervention.

Mid-year Report by Dr. Cahill

My fellowship proposal focused on the study of oligodendrogliomas and glioblastomas to gain insight into the mechanisms of chemoresistance. To this end, we are pursuing large-scale genetic analysis of human tumor samples. We have applied recently established gene expression profile algorithms to a glioma microarray expression dataset, identifying several interesting candidate genes for further follow up. Some are transcription factors which are thought to be involved in the developmental fate-determination of neural stem cell lineage selection. Therefore, identification of changes in expression may indicate they are misregulated in tumorigenesis. Others are cell surface markers for which we plan to pursue the development of immunohistochemical markers, to better diagnose the different histological subclasses of gliomas.

In addition, we have made intriguing observations regarding the molecular mechanisms of chemoresistance in human glioblastomas. In the last decade, combined radiation and temozolomide have become the standard-of-care for patients diagnosed with glioblastoma, conferring a modest but statistically-significant increase in median survival. To investigate the mechanisms of tumor progression, we pursued large-scale sequence analysis of all known protein kinases in eight human gliomas. This analysis identified a subset of tumors that had large numbers of somatic mutations within a specific local sequence context, suggesting the presence of a mutator phenotype in these tumors. Subsequently, inactivating mutations in the mismatch repair gene MSH6 were found in these tumors.

Interestingly, MSH6 inactivation and the mutator phenotype was only seen in tumors recurrent from treatment with temozolomide, mirroring a well-known in-vitro alkylator resistance phenomenon. Therefore, our data provide evidence that somatic inactivation of DNA repair pathways in human glioblastomas can mediate chemoresistance to temozolomide. These findings represent the first mutational evidence of this principle in any human tumor system, extending a well-established in-vitro model to the clinically relevant human treatment scenario. A paper detailing this work has been submitted and accepted for publication in the journal Cancer Research, with the acknowledged funding support of NREF, and we are currently following up on the implications of these findings.

I would like to thank the committee once again for the opportunity represented by the NREF Research Fellowship, and look forward to the upcoming months in the lab.

About Dr. Cahill

Dr. Dan Cahill is a resident in neurosurgery at the Massachusetts General Hospital in Boston, and a research fellow in the laboratory of Dr. David Louis in the Department of Pathology. He received his MD and PhD degrees from the Johns Hopkins School of Medicine in Baltimore, Maryland, with his graduate thesis work focusing on the molecular basis of chromosome instability and aneuploidy in human cancers. He was born and raised in Connecticut, attending Yale University as an undergraduate. He and his wife Jennifer currently live in the Beacon Hill neighborhood of Boston.