Two challenges in treating patients with estrogen-positive breast cancer (ER+) have been the inability to predict who will respond to standard therapies, and adverse events that cause therapy to be discontinued.
Now, an MD Anderson study has revealed new information about how the biomarkers retinoblastoma protein (Rb) and cytoplasmic cyclin E could indicate which patients will respond best to current first-line therapies. The study also discovered that combining the current therapy with autophagy inhibitors will result in using one-fifth of the dosage of the standard treatment, which could significantly reduce side effects associated with this therapy.
Standard treatment, consisting of palbociclib, often has adverse side effects and not all ER+ patients respond to the therapy. Palbociclib inhibits proteins called CDK4 and CDK6 (CDK4/6) and tumor cells escape this inhibition by activating autophagy, a process allowing cancer cells to thrive even when starved of nutrients. By combining palbocicilb with autophagy inhibitors in cells that express normal Rb and nuclear cyclin E, the dose of palbociclib was significantly reduced.
Khandan Keyomarsi, Ph.D., professor of Experimental Radiation Oncology, led a team that demonstrated how CDK4/6 and autophagy inhibitors synergistically induce cell senescence in Rb-positive cytoplasmic cyclin E-negative cancers. CDK4/6 inhibitors are approved by the Food and Drug Administration (FDA).
“Our findings could impact the majority of ER+ and HER2-negative breast cancers accounting for about 60 percent of advanced breast cancers,” said Keyomarsi. “We demonstrated for the first time evidence that Rb and cytoplasmic cyclin E status have a very strong effect on predicting response to the current standard first-line therapy for this population of patients, hormonal therapy plus palbociclib. We also discovered that by inhibiting the pathway such as autophagy that causes tumor cells to escape palbociclib growth inhibition, CDK4/6 inhibitor was more effective.”
Read more about this study in MD Anderson's newsroom.