Daniel A. Haber, MD, PhD

2012-2013 BCRF Project:
Breast cancer spreads to distant sites, including bone, liver and brain, primarily by metastasis through the bloodstream. While most cancer deaths are caused by such blood-borne dissemination of the primary tumor, metastasis is not readily studied in humans, since circulating tumor cells (CTCs) are extremely rare in the blood (estimated at one CTC per billion normal blood cells) and there are very significant technical hurdles that complicate their isolation and analysis. Dr. Haber's research team has developed a new microfluidic approach to the isolation of CTCs, which offers improved capture and subsequent molecular analysis of these rare cells. Using their "CTC-Chip" for isolation of tumor cells in the bloodstream of patients with breast cancer, Dr. Haber and his colleagues propose to study whether certain molecular biomarkers within CTCs can provide an early sign of response to hormonal therapy. This could allow determination, within a few days, of whether a tumor is responding to the given therapy, so that treating physicians can either continue or switch therapies faster. The investigators will also develop new approaches to study the types of genes that are expressed in these cells, since they are likely to provide key information about the process by which tumor cells enter the bloodstream. Such studies may one day provide new tools to monitor and ultimately prevent breast cancer metastasis.

During the last grant year, Dr. Haber's team has made significant progress in measuring the genes that are expressed in breast cancer circulating tumor cells. They have used next generation RNA sequencing technologies to obtain digital measurements of the genes that are active in these cancer cells that circulate in the blood stream, with the goal of comparing them with the genes that are expressed in the original breast cancer. Understanding which genes are activated during the process of blood vessel invasion by breast cancer offers the possibility of suppressing these and ultimately reducing the risk of metastatic spread of cancer.

Mid-year Progress: During the past six months, Dr. Haber's team has focused on a critical question in breast cancer biology: how do breast cancer tumor cells invade into blood vessels from the primary lesion and give rise to metastatic lesions? Experimental models have suggested that tumor cells that are part of "epithelial" glandular structures acquire abnormal migratory properties, transforming themselves into "mesenchymal" cells that invade into the bloodstream. This Epithelial to Mesenchymal Transformation (so-called "EMT") has never been clearly demonstrated in clinical specimens. Understanding whether EMT truly plays a major role in breast cancer metastasis is critical to efforts at both diagnosing and suppressing the spread of cancer from the primary lesion in the breast to distal sites of metastasis. To address this question, Dr. Haber's team made use of their specialized microfluidic technology to isolate circulating tumor cells (CTCs) from the blood of patients with breast cancer. They made the following observations.

First, primary breast cancers of all different types have relatively low but clearly detectable cells undergoing EMT. Second, tumor cells captured in the act of circulating in the bloodstream (CTCs) have greatly increased EMT. Third, these cells often travel in clumps or clusters, rather than as singular tumor cells in the circulation. Fourth, women with breast cancer who are responding to therapy tend to have a decrease in EMT, whereas those whose tumor is progressing on therapy have an increase in EMT. Lastly, specific pathways (some of which may be targeted by therapeutic agents) are evident in breast tumor cells undergoing EMT in the bloodstream of women with breast cancer. This work is now in press in the journal Science. Dr. Haber's ongoing studies are now aimed at further dissecting the genes expressed in CTCs and in exploring whether drugs under development can alter the EMT process associated with breast cancer metastasis.

Bio:
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.