"We found that 2C4 not only targeted HER-2/neu, but that it disrupted cell signaling among the entire HER family of proteins," said Dr. David Agus, lead author. "As a result of these lab studies, clinical trials are currently underway to test the safety and effectiveness of 2C4 in patients with breast and prostate cancer, as well as other solid tumors."

"Although HER-2/neu is a major target because it plays an important role in tumor growth, it's the growth signaling process that we ultimately want to block," said Dr. Agus.

Earlier studies by the same research group had shown that 2C4 blocked signaling activity within the HER network in prostate tumors grown in mice and significantly reduced tumor growth. In the current study, investigators wanted to see whether 2C4 would disrupt growth signals in breast cancer cells that did not express high levels of HER-2/neu and in prostate cancer tumors resistant to treatment with hormone antagonists.
Investigators evaluated the effectiveness of 2C4 both in cell lines established in culture and in human tumors grown in mice.

To explore the range of target activity of 2C4, investigators stimulated cancer cells by adding Heregulin or tissue growth factor-alpha and then treated the cell lines with either 2C4 or Herceptin. They found that 2C4 was effective in disrupting communication among HER-2 and HER-3 and between epidermal growth factor receptor and HER-2, whereas Herceptin was not effective.

"This means that 2C4 has the potential to turn off the entire HER-kinase signaling axis in solid tumors, as most solid tumors have some HER-2/neu on their cell surface, which is integral in the cell's signaling apparatus," commented Dr. Agus.

In animal work, the investigators injected mice carrying breast cancer tumors that expressed both high and low amounts of HER-2/neu with either Herceptin or 2C4. They found that Herceptin was just as effective as 2C4 against tumors that expressed high levels of HER-2 (shrinkage rate 77 percent with Herceptin, 80 percent with 2C4). The difference in drug activity was in tumors with low expression of HER-2/neu: Whereas Herceptin failed to slow tumor growth, 2C4 inhibited tumor growth by 59 percent.

"These findings suggest that 2C4 may work in breast cancers that do not express large amounts of HER-2/neu, which may ultimately mean that we can treat more patients with breast cancer," said Dr. Agus.

In hormone-independent prostate tumors, investigators found that 2C4 reduced tumor growth by 82 percent, with no reduction in tumor size achieved with Herceptin. The drugs were equally effective in reducing tumor growth in testosterone-dependent prostate tumors. "The potential of a biologic agent such as 2C4 to treat advanced prostate cancer is exciting, as there are presently few alternatives for treatment in these patients," said Dr. Agus.

A Phase I clinical trial started in October, 2001 to evaluate the safety and tolerability of 2C4 in patients with advanced cancers of the prostate, breast, ovary, lung, colon and other solid tumors.