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news.Scientists at The University of Texas MD Anderson Cancer Center have discovered that breast cancer patients with HER2-positive tumors who don't respond to Genentech's Herceptin may benefit from cocktail therapy that includes Herceptin along with one or more PI3K inhibiting agents.
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The 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 MD Anderson in HER2-positive breast cancer patients whose disease has progressed despite Herceptin (trastuzumab) 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,” said the study’s lead author, Dr Dihua Yu, professor in the center’s 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,” Dr Yu continued. “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, Dr 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.
PTEN is known to block the effect of a growth-promoting protein known as PI3K, which itself controls an oncogenic pathway that includes the cell proliferation kinases Akt and mTOR. Dr Yu decided to test what would happen if she administered an experimental drug that blocks PI3K, and thus mimics PTEN’s tumor suppressor activity.
In this study, the research group tested seven different PI3K inhibitors that are either used or under development for clinical trials. They found that one, RAD001 (everolimus), had better antitumor activity when combined with Herceptin than did Herceptin or RAD001 alone.
Another PI3K inhibitor, TCN-P (triciribine), showed significant benefit when used in combination with Herceptin. Even with a low dose of TCN-P, the combination therapy halted growth of PTEN-deficient HER2-positive breast tumors implanted in mice.