Our Science – Gril Website
Brunilde M. Gril, Ph.D.
Our laboratory studies the process of tumor metastasis, the movement to and progressive colonization of distant sites by tumor cells, focusing on breast cancer. Significant advances have been made to treat early-stage breast cancer; however, metastatic breast cancer, in particular brain metastases, remains incurable. Brain metastases occur in up to 35% of metastatic breast cancer patients whose tumors are 'triple-negative' (estrogen receptor, progesterone receptor and Her-2 negative) or overexpress Her-2. No effective treatment exists and brain metastases contribute significantly to patient morbidity and mortality. Our research team investigates brain metastases of breast cancer with a multifocal approach: (1) Development of mouse models of breast cancer brain metastases, (2) Identification of molecular alterations in brain metastases to identify potential targets, (3) Investigation of the molecular underpinnings of altered blood-brain barrier (BBB) permeability, (4) Investigation of potential brain permeable therapeutic compounds.
We performed molecular and experimental therapeutic studies investigating pathways that drive brain metastasis. For Her-2 overexpressing breast cancer, we published important work in JNCI, showing that lapatinib, a Her-2 and EGFR kinase inhibitor, can prevent brain metastasis formation by 53% in an experimental mouse model. This work is consistent with limited clinical trial data for lapatinib in the metastatic setting, supporting the relevance of our preclinical mouse models to predict drug efficacy in patients. Investigating the efficacy of the anti-angiogenic multi-tyrosine kinase inhibitor, pazopanib, we identified a new mechanism of action of the drug. We showed a potent preventive effect of the outgrowth of Her-2 brain metastases, targeting both the metastatic cells, through B-Raf signaling, and the metastasis-associated reactive astrocytes in the neuro-inflammatory microenvironment, through PDGFRβ.
In a separate but complementary project, we are studying the brain metastasis micro-environment and the vascular architecture of the blood-brain barrier (BBB). From our preclinical studies investigating multiple compounds, as well as from our BBB permeability studies using fluorescent markers in various brain metastasis mouse models, we identified drug delivery past the BBB as the main obstacle to treat this deadly metastatic site. We are currently investigating the structure and composition of the BBB as it is heterogeneously altered by a developing brain metastasis, in order to improve drug delivery and develop treatment options.
Our studies have involved successful collaborations with pharmacologists, radiation oncologists, pathologists and breast cancer advocates. These collaborations have enabled us to see the same disease from multiple angles, providing us with a perspective of the complexities associated with translational research and developmental therapeutics.
This page was last updated on 4/17/2014.