Clinicn Investigator, Full Prf Pathology, Mass General Research Institute

Pathologist Pathology, Massachusetts General Hospital

Austin L. Vickery, Jr. Professor of Pathology Harvard Medical School

M.D.; Ph.D. Stony Brook Medicine 2000

MD State University of New York, Stony Brook School of Medicine And Biomedical Sciences 2000

alk tyrosine kinases; brain tumors; carcinoma non-small-cell lung; gene products nef; gene rearrangement; genes erbb-1; in situ hybridization fluorescence; lung neoplasms; lung tumors; o(6)-methylguanine-dna methyltransferase; pancreatic tumors; proto-oncogene proteins c-met; pyrazoles; pyridines; receptor protein-tyrosine kinases; simian immunodeficiency virus

Our lab has focused efforts on translating highly complex molecular analyses of tumor genetics using novel technologies into clinical use. We have previously developed the SNaPshot genotyping assay, which has enabled Mass General to make personalized cancer medicine a priority.

We have a strong interest in the clinical implementation of genetic screening technologies that can help direct targeted therapies, focusing on lung, pancreatic and brain tumors.

Our recent contributions in the treatment of a subset of lung tumors with rearrangements of the ALK tyrosine kinase and with rearrangements of the ROS1 tyrosine kinase with a small molecule kinase inhibitor underscore the promise of personalized cancer care. Our long term goal is to develop high-throughput genetic screening approaches for all cancer patients.

To address this need, we have developed a novel next generation sequencing technique termed "anchored multiplex PCR (AMP)", that is especially powerful at detection gene fusion events from clinical specimens.

We have shown that AMP is a sensitive as FISH in diagnosing ALK, ROS1 and RET fusions in lung cancer, and does not require knowing both fusion partners. In addition, AMP can be used for genomic DNA target enrichment, and is scalable and cost effective. Current work focuses on ultrasensitive detection of mutations in blood and urine.

We have also continued prior studies of tumor heterogeneity, by studying gene amplification of receptor tyrosine kinases in glioblastoma. This work has revealed a new subclass of brain tumors with mosaic gene amplification of up to 3 kinases in distinct but intermingled cell populations within the same tumor. We are exploring the therapeutic implications of such driver gene heterogeneity in model systems of glioblastoma using patient derived cell lines and xenografts. A major effort here has been the development of multiplexed in situ genetic analysis using FISH. These techniques will allow us to analyze many more genes, and map copy number heterogeneity onto histology sections.

Our laboratory has also focused on human germline genetics, namely on copy number variation (CNVs). These polymorphisms involve copy number gains or losses of large genomic regions (kilobases up to several megabases), and were identified using high-resolution genomic microarrays to compare the genomes of phenotypically normal individuals.

Our continuing work is focused on the detailed structural analysis of CNVs using high resolution fluorescence microscopy imaging techniques, quantitative PCR and BAC sequencing. We have developed novel FISH probes based on deletion CNVs that can be used to determine genetic identity in situ.

These probes are being applied to chimerism analysis in transplantation and will aid in the study of engraftment, rejection, and graft versus host disease. Importantly, these probes are located on autosomes, so for the first time chimerism analysis can be performed in same sex transplants.