Determine how heparanase, a master regulator of cancer metastasis, affects the onset of brain metastasis via enzymatic and non - enzymatic functions, and at multiple levels, e.g., tumor cell adhesion, vascular cooption, disruption of the blood-brain-barrier, cytoskeletal dynamics, tumor cell extravasation/growth, and promoting chemotherapy resistance.
Brain metastasis remains the most devastating and feared consequence of cancer with more than 40 percent of all cancer patients developing brain metastasis. For example, patients with brain metastatic breast cancer (BMBC) have, even with the best available treatments, only a 20 percent one-year survival rate. BMBC is particularly common in breast cancers that are positive for epidermal growth factor receptor1 and 2 (EGFR and HER2), however, targeted therapies against BMBC, e.g., lapatinib - a EGFR/HER2 dual kinase inhibitor, are only minimally effective with response rates lower than those for extracranial metastases. The identification of mechanisms responsible for BMBC is imperative to develop new therapies.
By several pre-clinical studies, my laboratories have demonstrated that heparanase (HPSE) acts as a potent pro-tumorigenic, pro-angiogenic, and pro-metastatic enzyme. Heparanase is the only endoglycosidase in mammals which cleaves heparan sulfate (HS), the main polysaccharide of cell surface and tumor-surrounding extracellular matrix, into fragments retaining biological activity. An established role for heparanase is to release HS-bound growth and angiogenic factors stored in the extracellular matrix, and regulate their levels and potency, thus initiating many effects which drastically alter the metastatic outcome. These functions are mediated by enzymatically active heparanase. However, recent findings indicate that heparanase possesses functions which are independent of its enzymatic activity, and acts as an adhesion molecule and signal transducer. The therapeutic disruption of heparanase therefore provides an opportunity to block multiple pathways that control tumor-host interactions and are crucial for tumor growth and metastasis.
Our work has implicated heparanase as a promoter of brain metastasis whose activity is highest in cells metastasizing to brain. The enzyme is also produced by cells of the brain microenvironment in response to a brain neoplastic insult fostering metastatic growth. Further, we have demonstrated that heparanase is expressed in BMBC tissues, and functions as a target of EGFR/HER2 pathways affecting BMBC cell proliferation. Overall, these findings set the stage for developing therapies aimed at the heparanase/HS axis. To move toward this goal, we must gain a better understanding of the mechanisms of heparanase, which are poorly understood. By studying much broader roles for heparanase, which involve enzymatic and non-enzymatic functions, and deciphering these roles at distinct steps of brain colonization, we aim to demonstrate that heparanase regulates the cross-talk between BMBC and cells of the brain microenvironment, and initiates multiple effects which are critical for the development and progression of BMBC.