August 11, 2008

Monitoring Cancer Changes from the Blood

Microscopic image of a small cell in between 2 posts Electron microscope image of a single non-small cell lung cancer cell captured on the side of a micropost.NIBIB.

Researchers have come up with a new way to monitor cancer using a special microchip that isolates tumor cells from the patient's blood. The breakthrough could help doctors adjust to changes in tumors and personalize their patients' treatments.

If doctors could track the genetic changes in a tumor, they would know when to switch treatments and be able to stay a step ahead of a cancer’s progression. But taking multiple biopsies over the course of treatment is costly and uncomfortable for the patient, the tumors may not be accessible by surgery, and the procedure often doesn’t yield enough tumor cells for a proper analysis.

Tumor cells are also known to circulate in the blood of patients with metastatic cancer, but previous attempts to collect circulating tumor cells (CTCs) didn’t yield enough pure material for accurate analyses. A research team led by Dr. Mehmet Toner and Dr. Daniel Haber at Massachusetts General Hospital and Harvard Medical School have now designed a special microchip—called the CTC-chip—to capture tumor cells from blood. Their work was supported in part by NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB).

The business-card sized CTC-chip contains tens of thousands of microposts (miniature pillars) coated with antibodies that adhere to EpCAM, a protein found on the surface of cells in more than 85% of all cancers. These antibodies bind CTCs to the microposts as blood flows over the chip. The captured cells can then be analyzed further.

In the July 24, 2008, edition of The New England Journal of Medicine, the researchers demonstrated the effectiveness of the chip in tracking non–small-cell lung cancer. Mutations in the epidermal growth factor receptor (EGFR) gene determine whether non–small-cell lung cancer tumors will respond to medications called EGFR tyrosine kinase inhibitors, such as gefitinib (Iressa) and erlotinib (Tarceva). Unfortunately, most patients have a relapse within a year of beginning therapy. Behind relapse is another mutation in EGFR that renders tumors resistant to the medications.

The researchers used the CTC-chip to isolate tumor cells from the blood of 27 lung cancer patients. In general, an increase in the number of CTCs during treatment was associated with tumor progression. A reduction in the number of cells reflected a tumor response. When they sequenced the EGFR genes, the researchers found the expected EGFR tumor-activating mutation in CTCs from 11 of 12 patients. The mutation that confers resistance to tyrosine kinase inhibitors appeared in 9 of 14 patients (64%) whose tumors progressed, compared to 2 of 6 patients (33%) who responded to the medications.

CTC-chips could in theory capture CTCs from any type of cancer, depending on which antibodies are on the chip. “We want to improve this technology to create a diagnostic tool,” said Dr. Sunitha Nagrath, a researcher on the project. “It will be like a blood screening test for any onset of tumors, even in the absence of symptoms.”

The chips are currently being tested in prostate and lung cancer clinical trials. One day, doctors may use them to diagnose cancer early and guide their treatment decisions.

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