Combination Drug Holds Promise in Breast Cancer Treatment

In a new research by the Perelman School of Medicine of the University of Pennsylvania, the combination of the new breast cancer drug palbociclib with paclitaxel (Taxol) was able to reduce the size of tumors in almost half of the patients who are stricken with estrogen-receptor (ER) positive breast cancer.

Further study also showed why breast cancer develops resistance to palbociclib, which
commonly occurs in patients who are taking the drug for treatment.

Angela DeMichele, MD, MSCE, who is the senior author of the study, and the Alan and Jill Miller Associate
Professor in Breast Cancer Excellence in Penn's Abramson Cancer Center, says that the results of the study
indicate that both palbociclib and paclitaxel can be safely used together if used on an alternating dosing
schedule. The high response rate we saw suggests this combination may hold benefits for patients over
paclitaxel alone. Based on these results, a larger clinical trial to determine the benefits is warranted, says
DeMichele.

Palbociclib acts by inhibiting the activity of CDK4 and CDK6, which are enzymes that help in cell
proliferation and are upregulated in most cancers. The researchers hypothesized that this drug might be
good in combination with other drugs, such as paclitaxel, that try to kill cancer cells at a certain point in
the cell cycle. Palbociclib is able to halt the cycle before the cell completely divides, which means that
drug can make the cancer cells more vulnerable to a consequent dose of paclitaxel.

Breast Cancer Treatment

DeMichele and colleagues treated 27 patients with alternating doses of 75 mg per day palbociclib, which
was given daily for several days, and paclitaxel, given once a week. Around 44% of the patients had a
partial or complete response rate, and four additional patients had a stable disease for 6 months or longer.
The results suggested that the alternate dosing of the two drugs is safe to use for larger-scale trials.
Unfortunately, most patients experienced side effects such as neutropenia, which is a condition where
the white-cell-blood count is low. This is actually a common side effect of palbociclib and other drugs used
for cancer, but DeMichele says it is not threatening in general. In order to deal with this, the dose for some
of the patients was lowered.

In another study, DeMichele teamed up with palbociclib's maker, Pfizer. The aim this time was to
determine why breast cancer is able to develop resistance to the drug. Examining samples taken from a
patient who was undergoing treatment with palbociclib, the researchers found that while the tumors
were becoming resistant to the drug, the expression of several cell-cycle promoting genes such, as PLK1,
TOP2A, CDK1 and BUB1, were more than doubled. Cell cultures of tumor cells that have palbociclib
resistance also showed the same results.

It appears that while the drug blocks two important cell-cycle drivers, CDK4 and CDK6, other cell cycle
genes can compensate with increased expression levels to enable tumor cells to start dividing again, says
DeMichele. This implies that another drug that blocks these other cell cycle genes would be needed to be
able to prevent the resistance against palbociclib that is happening.