Reports of an experimental drug that slowed advanced breast cancer in a clinical trial have stirred excitement at a national research meeting and breathed new life into a cancer-fighting strategy that had seemed to falter.
In one study, the drug, palbociclib, doubled the length of time without disease progression in patients with metastatic estrogen receptor-positive breast cancer that had spread beyond the breast, compared with women who took only a hormonal treatment, researchers reported at the American Association for Cancer Research (AACR) in early April. Women in the study who received palbociclib also took the hormonal treatment, letrozole.
Palbociclib is the first of a new generation of a class of drugs that until now had failed to meet researchers’ expectations. Unlike many targeted cancer drugs, which block overactive switches called kinases, palbociclib attacks a downstream set of kinases that are the central recipients of these signals and which comprise key components of the molecular “cell clock.” The clock is made up of proteins called cyclins, which pair up with partners called cyclin-dependent kinases, or CDKs, to precisely control a cell’s cycle of rest, growth, and when it should divide to produce two new cells. Normally the clock monitors signals, and, through a system of “checkpoints,” ensures that the cell only divides when new ones are needed. Alteration of the clock’s proteins occurs nearly universally in cancer; when these proteins are mutated cancer cells become “deaf” to outside signals, ignore checkpoints, and proliferate endlessly to form and maintain tumors.
Dana-Farber researchers, among others, have pinpointed alterations in CDK4 and CDK6, and the cyclins with which they are paired, as promising targets for inhibitor drugs. Peter Sicinski, MD, PhD, in Dana-Farber’s Cancer Biology department helped lay the groundwork with discoveries that mice that lacked certain cyclin proteins could develop normally and were resistant to breast cancer. In addition, in mice with established breast cancers or leukemias, targeting cyclin-CDK4/6 complexes resulted in profound inhibition of tumor growth or tumor regression. But the first generation of CDK-blocking drugs didn’t fare well in clinical trials because their targeting of the CDK proteins wasn’t sufficiently specific.
The new drug, palbociclib, “was the first selective and safe inhibitor of CDK4/6 to be clinically available,” notes Geoffrey Shapiro, MD, PhD, who heads Dana-Farber’s Early Drug Development Center (EDDC). Shapiro says palbociclib’s manufacturer, Pfizer, wasn’t initially planning to sponsor further trials beyond the first safety study. But Shapiro proposed a small trial of the drug in a rare cancer, mantle cell lymphoma. The trial, headed by Shapiro and Dana-Farber oncologist Ann LaCasce, MD, reported results two years ago.
The study found substantial benefit in several of these patients, and, most importantly, confirmed that palbociclib was effectively hitting its CDK4/6 targets, leading Pfizer to sponsor further trials in several cancers. One was the breast cancer study that has garnered new attention to this class of drugs.
In another report at the AACR meeting, Shapiro and Sara Tolaney, MD, of the Susan F. Smith Center for Women’s Cancers at Dana-Farber, presented promising results of an early trial of a different CDK inhibitor, called bemaciclcib (LY2835219), in metastatic breast cancer. “The initial data, demonstrating tumor responses in 9 of 36 patients with advanced estrogen receptor-positive breast cancer, look even more striking than those for palbociclib,” says Shapiro, noting that the drug was used alone and not in combination with a hormonal treatment.
He adds that researchers in the EDDC are also testing a third CDK inhibitor drug made by Novartis and labeled LEE011 in melanoma and breast cancer. In addition, CDK inhibitors are now being combined with other targeted agents.
“I think it’s fair to say that the results with these newer CDK inhibitors represent a rebirth of interest in this strategy,” says Sicinski.