Effects of cyclin-dependent kinase inhibitors (CDK4/6) on pre-clinical models of bone metastases from breast cancer

Project objectives

Next-generation cyclin-dependent kinase (CDK4/6) inhibitors such as ribociclib, palbociclib, and abemaciclib have demonstrated significant clinical efficacy and low toxicity profiles in combination with hormone therapy in the treatment of ER+/HER- metastatic breast cancer. CDK4/6 kinases are activated upon binding to their regulatory protein, cyclin D, and regulate the G1 to S phases of the cell cycle through phosphorylation of the Rb protein. These drugs all exhibit high selectivity for CDK4/6, but differ in their inhibitory profiles for other kinases, which could translate into different biological effects on non-cancerous cells.

Breast cancer has a high propensity to metastasize to the bone and, in fact, a large percentage of patients undergoing treatment with cyclin-dependent kinase (CDK4/6) inhibitors present 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 have analyzed bone endpoints in patients treated with CDK4/6 inhibitors.

The specific objectives of the project are:

1) to analyze the direct effect of inhibitors of cyclin-dependent kinases (CDK4/6) on the differentiation and activity of human primary osteoclasts and osteoblasts

2) investigate a possible indirect, osteoblast-mediated antitumor effect of cyclin-dependent kinase (CDK4/6) inhibitors

3) evaluate the direct antitumor effect of cyclin-dependent kinase (CDK4/6) inhibitors on models of breast cancer bone metastasis

4) investigate the selectivity of cyclin-dependent kinase (CDK4/6) inhibitors for other kinases in osteoclast and osteoblastic cells

5) to retrospectively analyze skeletal outcome data (skeletal-related events, bone disease-free progression) in patients with breast cancer treated with hormonal therapy alone or in combination with cyclin-dependent kinase (CDK4/6) inhibitors

6) prospectively evaluate bone turnover markers in patients with breast cancer undergoing treatment with cyclin-dependent kinase (CDK4/6) inhibitors

Start and end date

January 2017 - ongoing

Project Manager

Prof. Giuseppe Tonini
Prof. Daniele Santini
Dr. Francesco Pantano

Research Team:
- Dr. Michele Iuliani
- Dr. Giulia Ribelli
- Dr. Sonia Simonetti

Coordinating institution of the project

Università Campus Bio-Medico di Roma

Funding source(s).

Novartis Farma SpA Largo U. Boccioni 1 - 21040 Origgio (VA)