Novel combinations and scheduling of chemotherapy and the CDK4/6 inhibitor palbociclib

Prof Chris Twelves (University of Leeds), Dr Steven Shnyder, Jade Spencer, and Prof Paul M. Loadman have received £131,803 from Pfizer and Breast Cancer Now to explore novel experimental combinations of existing breast cancer drugs with palbociclib. The identification of effective novel combination(s) will underpin new clinical trials with the potential to improve patient outcomes.

Palbociclib (Ibrance®, Pfizer) is an oral cyclin-dependent kinase (CDK) 4 and 6 inhibitor approved for use in combination with endocrine therapy in women with hormone receptor (HR) positive, HER2 negative metastatic breast cancer (BC).

As a single agent, palbociclib is essentially a cytostatic agent that acts by blocking CDK4/6 activity, preventing phosphorylation of the retinoblastoma (Rb) protein, therefore arresting cells in the G1 phase of the cell cycle. In addition to its established use in combination with endocrine therapy, there is the potential to exploit the ability of palbociclib to cause cell cycle arrest by synchronising the cells, to enhance the efficacy of cytotoxic chemotherapies such as anti-metabolites (e.g. the fluoropyrimidines and gemcitabine), taxanes (and other microtubule targeted agents) and anthracyclines. These cytotoxics are active in metastatic BC but this activity is limited and resistance common. There is, therefore, a need to improve the efficacy of chemotherapy, which remains the mainstay of systemic treatment for metastatic BC.