Breast cancer patients with HER2-positive tumors who don't respond to Herceptin (trastuzumab) may benefit from cocktail therapy that includes Herceptin along with one or more PI3K inhibiting agents, say researchers at the University of Texas M. D. Anderson Cancer Center.
Their findings, reported at the annual meeting of the American Association for Cancer Research (AACR), were made in cell culture and mice studies, but are so promising that a Phase I/II clinical trial will start at M. D. Anderson in HER2-positive breast cancer patients whose disease has progressed despite Herceptin treatment.
"More than half of patients with HER2-positive tumors don't respond to Herceptin as a single agent, and our research has shown us why that is and what might be done to help these patients," says the study's lead author, Dihua Yu, M.D., Ph.D., professor in the Department of Surgical Oncology.
"If this drug cocktail shows benefit, we hope to be able to identify those patients who won't respond to Herceptin before they start the treatment, and offer them a new and beneficial drug combination," Yu says. "Patients who don't respond to Herceptin have worrisome outcomes, so we hope this strategy will help them."
Combining PI3K inhibitors with existing therapies also might provide additional benefit in treating other breast tumor types.
In 2004, Yu and her research team reported that patients who don't respond to Herceptin have very low levels of PTEN in their breast tumors, whereas women who respond have higher levels of this protein. In normal cells, PTEN is a powerful tumor suppressor gene that helps control cell division. In about half of all of breast tumors (HER2-positive or not), however, PTEN levels are very low or the protein is completely missing.
It was known that when Herceptin, a monoclonal antibody, binds to the HER-2 protein on the outside of tumor cells it takes days for the protein to degrade. But Yu found that within 10 minutes of administration, Herceptin activated PTEN. This suggested that Herceptin works by rapidly mobilizing PTEN in addition to inhibiting HER-2 growth signals, she says.
Further research in Yu's lab demonstrated a correlation between Herceptin response and high levels of PTEN, and a link between lack of response and low or missing PTEN activation. Therefore, the presence of PTEN in a HER2-positive tumor is a powerful predictor of who will respond to Herceptin, Yu says.
The research group then dug a little deeper into the question of how Herceptin might function despite a lack of PTEN in a breast tumor.