关键词：大脑;乳腺癌;假设;转移;器官(解剖);硫酸盐;治疗
摘 要：The identification of brain metastatic breast cancer (BMBC) mechanisms responsible for brain metastasis is imperative to develop new therapies. The relevance of heparanase (HPSE) in cancer invasion and metastasis has been establishe. Heparanase is the only known functional endoglycosidase in mammals and degrades heparan sulfate (HS), the main polysaccharide component of growth factor-binding proteoglycans. The therapeutic disruption of heparanase/HS function provides the opportunity to block multiple signaling pathways which are crucial for tumor cell adhesion, survival, and growth within the target organ microenvironment. Our hypothesis is that heparanase represents a novel target for the development of therapies for BMBC treatment. We propose aims to determine HPSE regulation by MiR-1258 in BMBC and to Identify novel functions of SST0001 as synergies with lapatinib and/or miR-1258 in BMBC cell and animal models. We will address HPSE regulation at three levels: the first is to identify how heparanase is modulated translationally by miR-1258; the second is to study the efficacy of SST0001, a small-molecule glycol-split heparinoid, regulating post-translational HPSE activity; the third is to investigate synergies of the heparanase inhibitor SST0001 and lapatinib, and assess whether heparanase promotes the pathogenesis of BMBC by selectively foster resistance to lapatinib.