ROCK Has Potential as New Therapeutic Target in Breast Cancer

Roxanne Nelson

October 15, 2009

October 15, 2009 — A new target in breast cancer holds potential for preventing distant metastases, according to preliminary research highlighted at the American Association for Cancer Research (AACR) Frontiers in Basic Cancer Research Meeting in Boston, Massachusetts.

The new target, Rho-associated coiled-coil-forming protein kinase (ROCK), is pivotally involved in invasion by tumor cells and their evolution to metastasis, researchers told the meeting. In a mouse study, inhibiting ROCK signaling in the earliest stages of breast cancer decreased metastasis by approximately 85%.

Although the research is still very preliminary, the results suggest that inhibiting ROCK could be a viable therapeutic target in metastatic breast cancer, explained the study's first author, Sijin Liu, PhD, a research instructor at Tufts University School of Medicine in Boston, during a press briefing.

Their results showed that ROCK expression is higher in metastatic breast cancer cell lines and clinical tumors than in nonmetastatic cell lines and tumors. Inhibiting ROCK activity, either by using a specifically targeted agent or "ROCK targeted" small interfering RNA, decreases the migration of metastatic breast cancer cells and proliferation in vitro.

"Among primary tumors, those that do not have a metastatic presence are clearly less threatening," said Robert Weinberg, PhD, professor of biology at the Massachusetts Institute of Technology in Cambridge.

"When the primary tumor is originally diagnosed, the tumor may have already metastasized, and that is a process of which we know almost nothing about," said Dr. Weinberg, who was not involved in the study.

Important Role in Cancer

Accumulating evidence both in vitro and in vivo has demonstrated that the Rho/ROCK pathway might play an important role in the invasion and migration of cancer cells. The abnormal expression of ROCK is related to tumor metastases and correlates with poor clinical outcome, the authors note. Previous research has suggested that the activation of ROCK is associated with lymph node metastasis, lymph vessel invasion, and prognosis of patients with breast cancer.

"Breast cancer is the second most common type of cancer after lung cancer," said Dr. Liu, "And while the primary tumor causes considerable morbidity, metastasis is the cause of most breast-cancer-related death."

Metastasis to the bone is very common, he explained. "The mechanism is not well understood, and there aren't any effective treatments."

Inhibiting ROCK Prevents Metastasis

In this preclinical study, Dr. Liu and colleagues investigated the molecular mechanisms responsible for ROCK-mediated effects and the potential utility of ROCK inhibition as a therapeutic target. They evaluated the effect of ROCK inhibition on bone metastasis in breast cancer using a novel mouse model, and assessed the ability of an experimental inhibitor, Y27632, to block ROCK activity.

They found that Y27632 inhibited metastases to bone by 36%, compared with the control group. Only 5 of 14 tumors metastasized in the treated mice, whereas 8 of 12 tumors (67%) metastasized in the control group. In addition, the mass of metastatic tumors in the mouse skeleton was decreased by 77% (P < .05) in the animals treated with Y27632.

These data suggest that ROCK inhibition works by targeting a set of micro (mi)RNAs. The miRNA cluster 17–92 was elevated in metastatic cells, compared with nonmetastatic cells, and responded to treatment with Y27632. They also observed that inhibiting miRNA 17 decreased the invasion and migration of breast cancer cells in vitro and metastasis in vivo.

Currently, physicians generally follow the progress of the primary tumor, but the patient often succumbs to the metastases, said Tyler Jacks, PhD, president of the AACR. "So it is important to follow the progress of the metastatic tumor."

Aside from developing treatment for metastases, another goal is to prevent metastases in the first place, as this study has demonstrated, added Dr. Jacks, who moderated the session. "It wasn't completely prevented, but the results are exciting."

American Association for Cancer Research (AACR) Frontiers in Basic Cancer Research Meeting: Abstract A63. Presented October 8, 2009.

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