$1.17 million Department of Defense grant to develop new therapy to treat triple-negative breast cancer

Can Jagged-1 – a protein found on breast cancer cells – be a new target to treat triple-negative breast cancer? Jan Kitajewski believes so.

Kitajewski, Ph.D., a University of Illinois Cancer Center member and professor and head of physiology and biophysics at UIC, has received a three-year $1.17 million Department of Defense grant to develop a new therapy to treat triple-negative breast cancer, so named because it does not contain three of the most common types of receptors that fuel most breast cancer growth – estrogen, progesterone and the HER-2/neu gene.

About 40,000 women in the U.S. are diagnosed with triple-negative breast cancer (TNBC) each year. It is typically treated with aggressive chemotherapy or radiation, not with hormone therapy, the traditional course of action to fight most breast cancers. New targeted therapies for TNBC are “badly needed to improve the quality of life for patients, and many of them reside in our area,” Kitajewski said.

“Triple-negative breast cancer is more likely than other breast cancers to recur and spread to other parts of the body, such as the brain, lungs, liver or bones,” he said. “We need to find a way to block metastasis, because it is often difficult or impossible to treat once it spreads. In many cases this leads to death.”

Jagged-1 (or Jag1) is frequently produced by the TNBC tumors and activates Notch signaling, a form of cellular communication. The presence of Jag1 is typically associated with poor outcomes for patients. Notch signaling causes experimental tumors to grow better by promoting new tumor blood vessels, helping to deliver oxygen and nutrients to the tumor.

New data from the Kitajewski lab suggests Notch also promotes metastasis, the spread of the cancer to other organs. Researchers have tried to block all Notch signaling with chemical compounds, but these cause severe gastrointestinal toxicity.

Kitajewski and his laboratory have developed a new class of therapeutic proteins, called Notch decoys, that only block specific portions of the Notch signaling pathway, some only caused by Jag1. Tests have been conducted using Notch decoys on human tumors implanted into mice. Results have shown that Jag1-specific Notch decoys reduce tumor growth, tumor blood vessels and the ability of those vessels to carry blood and oxygen to the tumor, Kitajewski said. The treatment also did not cause gastrointestinal toxicity in the animals.

A new, more advanced Jag1-inhibiting Notch decoy, optimized for use in humans, has been developed by Kitajewski, his colleague, Naiche Adler, Ph.D., and his laboratory. The new grant will support the testing of the advanced Notch decoy in mice with tumors.

“We believe the Jag1-N1 decoy will have fewer side effects than aggressive chemotherapy, radiation, or other Notch inhibitors,” he said. “Most importantly, this therapy may block metastases to new organs, which would substantially reduce breast cancer mortality. We’re excited to receive this new funding to continue our work.”

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