Blood-brain Barrier break-throughs

[Jackie07]

Future Oncol. 2012 Feb;8(2):135-44.
Systemic treatment of brain metastases in HER2-positive breast cancer: current status and future directions.

Azim HA, Azim HA.
Source

Department of Clinical Oncology, Cairo University Hospital, Cairo, Egypt.
Abstract

In recent years, brain metastases have emerged as a main challenge affecting the morbidity and mortality of patients with HER2-positive metastatic breast cancer. In the era following trastuzumab, approximately 30% of these patients develop brain metastases. Trastuzumab does not cross the blood-brain barrier, hence its role is limited to controlling extra-CNS metastases. Lapatinib emerged as a potential candidate; however, its use as a single agent was associated with modest responses. Combination with capecitabine was associated with good results, particularly in patients with newly diagnosed brain metastases. In this article, we discuss the role of trastuzumab and lapatinib in patients with HER2-positive breast cancer with brain metastases. We also highlight the complex structure of the blood-brain barrier and elucidate different potential strategies that could be useful in improving drug delivery.


Curr Cancer Drug Targets. 2012 Mar;12(3):210-7.
New target therapies for brain metastases from breast cancer.

Metro G, Fabi A.
Source

Division of Medical Oncology, Santa Maria della Misericordia Azienda Ospedaliera di Perugia via Dottori, Perugia, Italy.
Abstract

Central nervous system (CNS) metastases from breast cancer (BC) represent an important cause of disease-related morbidity and mortality. For BC patients who develop CNS metastases, local control measures (both surgery and radiation) are essentially palliative and usually poorly effective, with systemic therapies often failing to achieve optimal control mainly due to the presence of the blood-brain barrier which hampers adequate penetration of therapeutic agents into the brain. However, recent evidence suggests that the status of the human epidermal growth factor receptor-2 (HER2) strongly influences the incidence of CNS metastases and the survival of BC patients from the time of development of CNS metastases, with HER2-positive (HER2+) patients generally experiencing higher rates of CNS metastases and prolonged overall survival compared to patients with HER2-negative disease. This phenomenon likely reflects the difficult CNS drug-penetration and improved control of extra-CNS disease following the clinical use of the anti-HER2 monoclonal antibody trastuzumab. Importantly, this HER2-based survival difference has important implications when planning the optimal treatment of BC patients with CNS metastases. To date, although no systemic therapy has been specifically approved for the treatment of CNS metastases from BC, several targeted agents are being clinically developed for this purpose. In the present review we will discuss the targeted therapies that are under investigation for the treatment of CNS metastases from BC, highlighting the different implications based on whether a given agent is being developed to target CNS metastases from HER2+ or HER2-negative breast cancer.

Prog Neurol Surg. 2012;25:110-4. Epub 2012 Jan 6.
Role of chemotherapy on brain metastasis.

Lee SH.
Source

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. sehoon.lee119@gmail.com
Abstract

Cytotoxic chemotherapy has been considered ineffective for brain metastasis, traditionally because of poor penetration across the blood-brain barrier. However, cytotoxic chemotherapy could be effective in some specific situation, e.g. macroscopic brain metastasis of chemosensitive disease, such as small cell lung cancer, germ cell tumor and breast cancer. Recently, tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR) (gefitinib and erlotinib) or human epidermal growth factor receptor 2 (HER2) (lapatinib) have a promising activity to brain metastasis of lung cancer with activating EGFR mutations or breast cancer with HER2 over expression. More molecular targeting agents will also be used against brain metastasis with the advance of understanding of molecular mechanism of cancer.
Pharm Res. 2012 Mar;29(3):770-81. Epub 2011 Oct 20.
Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer.

Taskar KS, Rudraraju V, Mittapalli RK, Samala R, Thorsheim HR, Lockman J, Gril B, Hua E, Palmieri D, Polli JW, Castellino S, Rubin SD, Lockman PR, Steeg PS, Smith QR.
Source

Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1406 Coulter Drive, Amarillo, Texas 79106, USA.
Abstract

PURPOSE:

Lapatinib, a small molecule EGFR/HER2 inhibitor, partially inhibits the outgrowth of HER2+ brain metastases in preclinical models and in a subset of CNS lesions in clinical trials of HER2+ breast cancer. We investigated the ability of lapatinib to reach therapeutic concentrations in the CNS following (14)C-lapatinib administration (100 mg/kg p.o. or 10 mg/kg, i.v.) to mice with MDA-MD-231-BR-HER2 brain metastases of breast cancer.
METHODS:

Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography.
RESULTS:

(14)C-Lapatinib concentration varied among brain metastases and correlated with altered blood-tumor barrier permeability. On average, brain metastasis concentration was 7-9-fold greater than surrounding brain tissue at 2 and 12 h after oral administration. However, average lapatinib concentration in brain metastases was still only 10-20% of those in peripheral metastases. Only in a subset of brain lesions (17%) did lapatinib concentration approach that of systemic metastases. No evidence was found of lapatinib resistance in tumor cells cultured ex vivo from treated brains.
CONCLUSIONS:

Results show that lapatinib distribution to brain metastases of breast cancer is partially restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies between tumors.