Daniel A. Haber, MD, PhD
Massachusetts General Hospital Cancer Center
Kurt J. Isselbacher/Peter D. Schwartz Professor of Oncology
Harvard Medical School
The Haber laboratory focuses on understanding the fundamental genetics of human cancer, from inherited mutations that confer familial predisposition to genetic mutations that are acquired by tumors themselves and may render them susceptible to specific targeted drug therapies. For example, we have identified mutations in the EGFR gene that confer dramatic sensitivity of some lung cancers to drugs that inhibit that pathway, pointing toward the importance of genetic classification of common epithelial cancers in applying novel targeted therapies. We have also collaborated with the bioengineering team led by Dr. Mehmet Toner, the molecular biology group of Dr. Shyamala Maheswaran, and the Massachusetts General Hospital Cancer Center clinical disease centers to develop, characterize and apply a microfluidic device capable of isolating rare circulating tumor cells (CTCs) in the blood of patients with cancer. This new technology offers the promise of 1) noninvasive monitoring of cancers during their treatment for the emergence of drug resistance; 2) early detection of invasive cancers; and ultimately 3) understanding and preventing blood-borne spread of cancer.
Daniel A. Haber, MD, PhD
* co-directed with Shyamala Maheswaran, PhD
Our laboratory is interested in the genetics of human cancer. Current projects include the use of a microfluidic device to capture circulating tumor cells (CTCs) and its application in molecular-directed therapy and in the study of human cancer metastasis. We also have a long-standing interest in the genetics of the pediatric kidney cancer Wilms tumor.
Circulating Tumor Cells and Molecular Genetics Underlying Targeted Cancer Therapeutics
Activating mutations in the epidermal growth factor receptor (EGFR) were identified in our laboratory in the subset of non-small cell lung cancer (NSCLC) with dramatic responses to the tyrosine kinase inhibitor gefitinib. We have studied mechanisms underlying such oncogene addiction, as well as the pathways that lead to the acquisition of resistance and the application of irreversible inhibitors of EGFR in circumventing mutations that alter drug binding affinity. We have also explored other genetically driven drug susceptible subtypes, including MET amplification in gastric cancer and EML4-ALK translocations in NSCLC. In collaboration with the Benes, Engelman and Ramaswamy laboratories, we are overseeing a large-scale collaboration between the Mass General Cancer Center and Sanger Institute to screen novel targeted compounds for sensitivity patterns across a very large number of cancer cell lines. This effort is aimed at recapitulating the genetic heterogeneity of human malignancies. This screen recently led to discovery of sensitivity of Ewings Sarcoma to PARP inhibitors. In collaboration with the Settleman laboratory, we identified the BMP/Wnt pathway as highly activated in mutant KRAS-dependent colon cancer cells, pointing to its downstream effector MAP3K7 (TAK1) as a promising drug target in this recalcitrant form of colorectal cancer.
We are collaborating with the Toner and Maheswaran laboratories to characterize novel microfluidic devices capable of isolating CTCs from the blood of cancer patients. One version of these CTC-Chips relies upon blood flow through a specialized chamber coated with antibody to the epithelial marker EpCAM to capture CTCs with high efficiency. We have shown that the number of captured CTCs correlates with clinical evidence of tumor response, and that the cells can be used to define molecular markers characteristic of the underlying malignancy, including EGFR mutations in lung cancer and PSA expression and TMPRSS2-ERG translocations in prostate cancer. Most recently, we have applied next generation single-molecule RNA sequencing to identify Wnt2 as a suppressor of anoikis pathways in circulating epithelial cells. Suppressing this pathway may reduce metastatic potential in pancreatic cancer cells. We have also identified subsets of satellite RNAs that are aberrantly expressed in pancreatic and other tumors and that may constitute novel biomarkers in CTCs and other tumor specimens. Current efforts are directed at potential applications of CTC capture in early detection of cancer, monitoring tumor genotypes over the course of treatment, and biological characterization of CTCs themselves. In addition, we are investigating the mechanisms underlying tumor invasion, including epithelial-to-mesenchymal transition.
Wilms tumor is a pediatric kidney cancer that has been linked to inactivation of the WT1 gene, encoding a developmentally regulated zinc finger transcription factor. We have recently identified a novel Wilms tumor suppressor gene located on the X chromosome, WTX. Mutations in WTX are found in 30% of sporadic Wilms tumors, mutually exclusive with WT1 and, like WT1, WTX is selectively expressed in early renal precursors. Remarkably, WTX display one-hit inactivation, targeting the single X chromosome in males or the single active X chromosome in females. In collaboration with the Bardeesy and Rivera laboratories, we have shown that WTX inactivation in the mouse leads to major defects in mesenchymal differentiation.
MGH Hotline 9.24.10 The Liberty Hotel ballroom filled quickly on the evening of Sept. 10 as the MGH Development Office hosted a viewing of the Stand Up to Cancer television broadcast.
The 2015 NPLS will focus on Frontiers in Cancer Research, and cover some of the latest advances in the understanding and treatment of cancer. The conference brings together some of the world’s leading scientists and physicians who have made dramatic breakthroughs in cancer therapy. Massachusetts General Cancer Center Director, Dr. Daniel Haber, is a keynote speaker.
The 2015 NPLS will focus on Frontiers in Cancer Research, and cover some of the latest advances in the understanding and treatment of cancer. The conference brings together some of the world’s leading scientists and physicians who have made dramatic breakthroughs in cancer therapy. Mass General Hospital Cancer Center Director, Dr. Daniel Haber, is a keynote speaker.