Abstract 4447: Nanoformulation of lapatinib for HER2-positive breast cancer patients with brain metastasis

Despite HER2-targeting agents having a reduced risk of distant relapse in early-stage breast cancer and improved systemic control in metastatic breast cancer, relapse or progression in the brain is a common and serious concern for mortality and morbidity in these HER2-positive breast cancer patients. Currently, radiation is the only effective therapy for these patients with various clinical outcomes. Thus, there is a significant unmet need to develop new therapeutic modalities to improve treatment efficacy for these patients, especially for patients who have failed radiation therapy. The objective of this project is to develop a novel nanoformulation of lapatinib for the treatment of HER2-positive breast cancer patients with brain metastasis. Lapatinib is the only FDA-approved small molecule tyrosine kinase inhibitor targeting both HER2 and epidermal growth factor receptor (EGFR). Lapatinib anecdotally induces objective response in HER2-positive breast cancer patients with brain metastasis. Current preclinical and clinic data suggest that lapatinib has limited and variable penetration through the blood-brain barrier, which is also affected by large inter-patient variations in the bioavailability of oral formulation of lapatinib. Dr. Lam9s laboratory has developed a novel nanoparticle technology using oligocholic acid based micelles (telodendrimers) to load a high dose of hydrophobic drugs for cancer treatment. We have generated a stable nanoformulation of lapatinib with drug loading up to 10 mg per mL. The average particle size is less than 20 nm in diameter, which is desirable for tumor targeting due to the preferential drug accumulation at the tumor site via the enhanced permeation and retention (EPR) effect. We are currently optimizing and characterizing the physicochemical properties of several lapatinib-loaded nanoformulations. The most stable and efficacious nanoformulation of lapatinib will be selected for further preclinical testing using in vitro and in vivo models of HER2+ breast cancer. This nanoformulation of lapatinoib will be suitable for intrathecal injection as it is not affected by individual variations in oral bioavailability and penetration through the blood brain barrier. If successful, we would design a phase I/II clinical study to determine the safety and efficacy of this new nanoformulation of lapatinib for HER2+ breast cancer patients with refractory brain metastasis or meningeal disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4447. doi:10.1158/1538-7445.AM2011-4447