Combination approach better targets breast cancer tumors with PIK3CA gene mutations.
A combination drug therapy uses a dual attack to effectively target and kill breast cancer cells that carry a specific gene mutation.
The results of a preliminary study published in Science Translational Medicine showed that a combination regimen of the investigational drug ABT-737 and a mammalian target of rapamycin (mTOR) inhibitor shut down 2 of the key survival strategies in cancer cells.
PIK3CA gene mutations are found in approximately 35% of newly-diagnosed breast cancer tumors. Furthermore, after exposure to standard treatments, even more patients can develop the mutation.
“This work reflects several careful studies to not only define the mechanism of action of the combination therapy, but also to explore the therapy’s activity in cellular animal models,” said senior author Kris C. Wood, PhD. “Our preliminary findings suggest that this therapy may be a safe and effective approach in human breast cancer patients who carry this mutation.”
To begin the study, investigators first asked how to improve the efficacy of ABT-737; a drug that inhibits a cellular pathway involved in apoptosis.
Initial tests showed that the agent had little effect on a variety of solid cancer tumor cells. However, when the investigators added a second agent designed to inhibit the mTOR pathway, a subset of breast cancer cells died at a substantial rate.
Prior studies have shown that breast cancers with PIK3CA gene mutations do not respond well to drugs that target PI3K or mTOR. To address this issue, the investigators found that PIK3CA-mutated tumors are uniquely able to compensate when either ABT-737 or an mTOR inhibitor is used alone, relying on the cell survival pathway that is not targeted by the drug to stay alive, according to the study.
When the drugs were used in combination, they became lethal, and shut down both cell survival pathways, causing the tumor cells to die.
“One of the compelling results of the study it that we can use very low doses of bother therapies to achieve strong results,” said lead author Grace R. Anderson. “At such low doses, the side effects could be minimized.”
To advance the clinical trial findings, studies are being planned that use currently-approved therapies or investigational drugs, such as Navitoclax, according to the authors.