Daniel A. Haber, MD, PhD
Director, Massachusetts General Hospital Cancer Center
Isselbacher/Schwartz Professor of Oncology
Harvard Medical School
Investigator, Howard Hughes Medical Institute
Massachusetts General Hospital
2013-2014 BCRF Project:
(The J.C. Penney Award)
In the last grant year, Dr. Haber developed a new version of his microfluidic chip, which dramatically enhances its capabilities in purifying breast cancer cells from the blood circulation. Instead of fishing out the tumor cells using imperfect capturing markers, Dr. Haber’s team can now effectively and delicately remove billions of normal blood cells from a blood specimen, while leaving behind the few intact tumor cells. This new technology now allows Dr. Haber’s team to perform detailed studies as to the identity of circulating breast cancer cells, their unique properties and their vulnerabilities. Ultimately, these researchers will seek to culture these cancer cells in the laboratory to study their drug sensitivity patterns, which may be predictive of patient response.
Dr. Haber has two major goals for the next funding period, both taking advantage of the new CTC‐Chip technology, which allows isolation of individual CTCs from the blood: 1. His team will compare the genes in breast CTCs that have spread to bone vs those that have spread to the liver to understand the basis of this difference. Identifying the key molecules that attract cancer cells to these distant tissues may offer the possibility of suppressing this “homing” signal and thereby suppress metastasis 2. They will isolate viable breast CTCs from the blood and grow them in the laboratory. If successful, this would enable the researchers to grow tumor cells from individual patients at distinct points in their treatment, ultimately allowing modeling of drug responses in the laboratory and individualizing therapy for each patient based on the properties of their own tumor cells.
During the 2013 granting period, Dr. Haber’s group made significant progress in characterizing circulating tumor cells (CTCs) shed by breast cancer. These cells are rare, but they hold the key to understanding, monitoring and ultimately preventing the metastatic spread of breast cancer. They have developed a novel microfluidic platform which enables depletion of normal blood cells from a tube of blood, leaving behind intact CTCs, which can be studied in detail (Ozkumur et al., Science Translational Medicine 2013). They have studied the process of Epithelial to Mesenchymal Transition (EMT), whereby stationary cancer cells become more migratory and invasive into the bloodstream. They have shown that CTCs undergo this fundamental change in the blood of women with breast cancer, and this change is modulated by the administered therapy (Yu et al., Science 2013). Using advanced RNA sequencing technologies, they have defined molecular changes in CTCs that underlie this change in breast cancer cell fates. Finally, using a new microfluidic device, they have successfully achieved the culture of breast CTCs in the laboratory. This is the first time that CTCs isolated from the blood of women with breast cancer were expanded in the laboratory, producing enough cells for detailed molecular analysis. The researchers were able to test 1,000 cancer genes for the presence of mutations in these CTC cell lines and correlate identified mutations with sensitivity to anti-cancer targeted drugs. While the culture of CTCs from patients with breast cancer still requires considerable optimization before it can become a clinical resource, this research “proof of principle” raises the possibility that in the future, CTCs may be cultured from the blood of women with cancer, tested for many cancer-associated mutations that drive their proliferation, and analyzed for sensitivity to drugs targeting these genes, thereby achieving truly individualized rational therapy of breast cancer.
Dr. Daniel Haber is Director of the MGH Cancer Center and the Isselbacher/Schwartz Professor of Oncology at Harvard Medical School. His laboratory interests have focused on cancer genetics, including the etiology of the pediatric kidney cancer Wilms tumor and genetic predisposition to breast cancer. Recently, his laboratory reported that lung cancers with activating mutations in the epidermal growth factor receptor (EGFR) are uniquely sensitive to tyrosine kinase inhibitors that target this receptor. This observation has had important implications for the genotype-directed treatment of non-small cell lung cancer, and more broadly for strategies to identify critical genetic lesions in cancers that may serve as an "Achilles heel" and be suitable for molecular targeting.
In collaboration with Dr. Mehmet Toner's laboratory, Dr. Haber's laboratory has recently established the application of a novel microfluidic technology for quantifying and purifying circulating tumor cells from the blood of patients with various epithelial cancers. This new application has potentially profound implications for early diagnosis of cancer and for noninvasive molecular profiling of cancers during the course of therapy.