Project Objectives

Third generation cyclin-dependent kinase inhibitors (CDK4/6), such as ribociclib, palbociclib and abemaciclib, have shown remarkable clinical efficacy and low toxicity profiles in the treatment of metastatic breast cancer ER+/HER-. Activated CDK4/6 kinases, following their binding to cyclin D, regulate phases G1 to S of the cell cycle by phosphorylation of the Rb protein. Interesting, ribociclib, palbociclib and abemaciclib show a high selectivity for CDK4/6, but different profiles of inhibition on other kinases, which could result in a different biological action on healthy cells.

Breast cancer has a high propensity to metastasize to bone and, in fact, a large percentage of patients candidate to CDK4/6 inhibitors treatment have skeletal metastases.

However, to date, there are no preclinical studies that have evaluated the direct impact of these drugs on the bone tumor microenvironment, nor clinical trials that reported data about bone end-points in patients treated with CDK4 /6 inhibitors.

The specific objectives of the project are:                                

1) to analyze the direct inhibitor effect of CDK4 / 6 inhibitors on human primary osteoclasts and osteoblasts differentiation and activity

2) to investigate a possible indirect antitumor effect of CDK4 / 6 inhibitors mediated by osteoblasts

3) to evaluate the direct antitumor effect of CDK4 / 6 inhibitors on models of bone metastases from breast cancer

4) to investigate the selectivity of CDK4/6 inhibitors for other kinases in osteoclastic and osteoblastic cells

5) to retrospectively analyze skeletal outcome data (time to first SRE development, time to bone metastasis progression) in breast cancer patients treated with hormone therapy alone or in combination with CDK4/6 inhibitors

6) to prospectively evaluate bone turnover markers in patients treated with CDK4/6 inhibitors

Start/End Date

January 2017 – ongoing

Principal Investigators

Prof. Giuseppe Tonini

Prof. Daniele Santini

Dr. Francesco Pantano

Research Team

Dr. Michele Iuliani

Dr. Giulia Ribelli

Dr. Sonia Simonetti

Host Institution

Campus Bio-Medico University of Rome

Other Institutions involved

None

Source of funding

Novartis Farma S.p.A Largo U. Boccioni 1 - 21040 Origgio (VA)