According to research presented at the AACR -NCI- EORTC International Conference on Molecular Targets and Cancer Therapeutics, further progress has been made regarding the treatment of melanoma and breast cancer. Preclinical studies showed promising results and researchers have recently launched phase 1 clinical trials to evaluate the safety and toxicity of LEE011, an inhibitor of cyclin -dependent kinases ( CDK ) 4/6.
Studies have shown that many cancers occur because a protein that functions as a tumor suppressor (called retinoblastoma) is inactivated due to an increased activity of CDK4 and 6. This protein, CDK4 /6, is controlled by cyclin D and cyclin D expression is increased by the activity of BRAF and PIK3CA, proteins involved in melanoma and breast cancer.
Researchers used BRAF and PIK3CA as therapeutic targets in breast cancer and melanoma treatment but unfortunately although initially respond to treatment, the patients eventually develop resistance. William Sellers, MD, vice president and global head of oncology at the Novartis Institutes for Biomedical Research in Cambridge , Mass. , said that the optimization of chemistry lead to the discovery of LEE011 and that so far, it is the most selective inhibitor of CDK4 /6. He explained that by using the latest cancer genomics, they were able to identify the indications and the drug combinations of LEE011. According to Sellers, LEE011 is able to prevent the emergence of resistance to the partner compound that would otherwise occur if the compound would be dosed without LEEo11.
Based on these results, the pharmaceutical company Novartis launched several phase 1 clinical trials in adults and a phase 1 clinical trial in pediatric patients. Sellers said that until now studies have shown that LEE011 is well tolerated and has excellent pharmacokinetic properties. Laboratory experiments conducted by Sellers and his team showed that this drug prevents the growth of tumor cells ( it appears that LEE011 inhibit tumor cells in a critical phase called G1).
Further experiments on mice showed that LEE011 has a robust antitumor activity in melanoma when tested in combination with another BRAF inhibitor, LGX818 . The same results were obtained when LEE011 was tested in combination with PIK3CA inhibitor, BYL719, an investigational drug for breast cancer.
Researchers are now investigating LEE011 in adult patients as a single agent to see which is the drug works in cancers that are dependent on CDK4 /6 as head and neck cancers, certain lymphomas and liposarcoamas. Also, the drug is tested in a study in pediatric patients for the treatment of malignant rhabdoid tumors and neuroblastoma.