New Target Identified for Reducing Metastasis


Key Points

  • CYFIP1 stabilizes the protein complex in its relationship with WASF3.
  • The research team is currently working with pharmacists to develop stapled peptides to disconnect WASF3 from CYFIP1.
  • The scientists noted that the cells' ability to proliferate was unimpeded—only metastasis is affected by this relationship. 

A protein that is constantly expressed by cancer cells and quiescent in healthy cells appears to be a solid target for reducing cancer's ability to spread, scientists reported.

The WASF3 protein enables cancer cell invasion, and by interrupting its relationship with another protein, CYFIP1, which helps WASF3 keep its form and function, scientists have suppressed the ability of highly invasive human breast and prostate cancer cells to metastasize through an artificial surface that mimics blood vessel invasion. Their findings were published by Teng et al in Cancer Research.

“Ninety-five percent of all cancer deaths are due to metastasis, not due to the primary cancer,” said John Cowell, PhD, DSc, FRCPath, Professor of Pathology at the Medical College of Georgia at Augusta University and Associate Director for Basic Science at the University's Cancer Center. “If metastasis is your target, this is the protein you should be targeting.”

Wide Range of Applicability

The study showed that interfering with the relationship between WASF3 and CYFIP1 is deadly to WASF3. “CYFIP1 stabilizes the protein complex,” Dr. Cowell said. “The whole thing has to be together to be stable; otherwise it just falls apart.”

The WASF3 finding has applicability to a wide range of cancers, including other common cancers such as melanoma and pancreatic cancer, Dr. Cowell said.

His team first suspected the role of WASF3 in metastasis in 2002, when they first identified the WASF3 gene in a child with neuroblastoma. They then used mass spectroscopy to discover the proteins that WASF3 interacts with and found CYFIP1 high on the list.

Role of Peptides

More recently, his team worked with Eileen J. Kennedy, PhD, Assistant Professor at the University of Georgia College of Pharmacy, to develop stapled peptides that essentially disconnect WASF3 from the stabilizing force of CYFIP1. “It's the same effect. WASF3 goes away and, guess what, so does invasion,” Dr. Cowell said.

There is already one clinical trial underway for a peptide that interrupts the interaction between two other proteins. “So the therapeutic pendulum is swinging toward these peptides,” Dr. Cowell said.

The scientists note that the cells’ ability to proliferate was unimpeded. “Cells can and will grow at the primary site,” Dr. Cowell said. More traditional cancer therapies, including drugs and/or surgery, often are effective at removing a large mass that can result from such proliferation. However, there are currently no therapies available that target metastasis or WASF3 specifically, Dr. Cowell said.

While the entire WASF family of proteins has been implicated in healthy cell movement, only WASF3 seems to help cancer cells invade and metastasize. When the scientists worked with WASF1 and WASF2, which also bind to CYFIP1, the cancer cells' ability to invade was not affected.

Dr. Cowell noted that there are likely many genes involved in metastasis, and many likely intersect at some point. “The critical thing is, all you have to do to a cancer cell is kill the function of this protein, and it can't metastasize.”

The scientists are finding similar results in mice with breast cancer and in zebrafish given human cancer cells. Future studies will need to examine the stability and toxicity of the stapled peptides. “We are at is the proof-of-principle stage in establishing that targeting this particular complex has the potential to suppress invasion or metastasis,” Dr. Cowell concluded.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.