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Circulating Tumor Cells Uncover Secrets of Drug Resistance

By BCRF | October 6, 2016

BCRF investigator, Dr. Daniel Haber studies patients with advanced, drug resistant ER-positive breast cancer in search of circulating tumor cells that could reveal new therapeutic options

Scientists do not fully understand why tumor cells become resistant to therapy, but current research supports the possibility that it involves treatment-induced molecular or genetic changes that reprogram the cell, allowing it to survive in the presence of drugs.

Screening blood for clues about cancer

Fluid biopsy is an exciting new technology that may someday replace or augment the use of surgical tissue biopsy for cancer detection and patient monitoring during or after treatment. The technology works by isolating whole circulating tumor cells (CTCs), tumor DNA or other pieces of tumor cells from blood. Coupled with advanced DNA sequencing and cell biology technologies, scientists are able to uncover new secrets of tumor behavior based on tumor factors isolated from blood.

In collaboration with colleagues at Massachusetts General Hospital, Harvard Medical School and Massachusetts institute of Technology, BCRF investigator, Dr. Daniel Haber has been employing microfluidics technology to study rare circulating tumor cells to understand the underlying biology of drug resistance and metastasis.

CTCs are tumor cells that are shed from the primary tumor and enter the lymph or vascular circulation. The research team recently published new findings in the journal Nature that reveal a property of CTCs that may provide insight into drug resistance in patients with advanced ER-positive/HER2-negative breast cancer. The study showed that the patients’ tumors produced CTCs that were able to convert from fast growing to slow growing and back again.

Is CTC plasticity driving drug resistance?

The research team reported high levels of HER2-positive (HER2+) CTCs in heavily treated patients whose breast cancers had produced little or none of the HER2 protein (HER2-). When the researchers isolated the HER2+ CTCs and cultured them in the lab, they discovered that the HER2+ cells replicated into both HER+ and HER2-negative (HER-) cells and visa-versa and that the different groups of cells had distinct properties. The HER+ CTCs were fast growing and unlike HER2+ breast cancers that are treatable with HER2-targeted drugs, the acquired HER2+ CTCs did not seem depend on HER2 to survive and were less responsive to HER2 targeted therapy alone. The HER2- CTCs grew more slowly and were less responsive to common chemotherapies but were treatable with a targeted therapy called GSI, which blocks a growth-promoting pathway called NOTCH.

Clinical trials are currently testing anti-HER2 therapies in HER2-negative breast cancers that have acquired HER+ CTCs with the hope of preventing drug resistance and metastasis. Dr. Haber's research findings support the use of combination therapies for two reasons: 1) HER2-positive CTCs from these tumors do not necessarily depend on HER2 to grow  and 2) The ability of HER2-positive CTCs to convert to HER2- negative and vice versa suggest that combination therapies are likely to be needed to treat these advanced breast cancers and prevent drug resistance.

Liquid biopsy technology has the potential to dramatically change how cancer is detected and clinically managed. BCRF is supporting several investigators who are pioneers in the field along with Daniel Haber and his colleagues. Read our previous stories about how Dr. Ben Park at Johns Hopkins and the research team of Drs. Peter Kuhn and James Hicks at the University of Southern California are working to advance the technology in clinical applications.