DDIS-18. THE PROTEASOME: TARGETING THE NF-κB PATHWAY IN THE TREATMENT OF GLIOBLASTOMA MULTIFORME

Abstract

Glioblastoma Multiforme is a rare neoplastic disease of the brain that is known for its rapid aggressive growth and its poor clinical outcomes secondary to limitations in treatment efficacy. As such, the discovery of new agents to hinder and slow the proliferation of GBM is paramount for the eventual eradication of the disease. One such pathway of targeting is the proteasome, as it provides a unique and novel means of targeting the growth and metastasis of aggressive forms of GBM. Expression of the proteasome is integral for the canonical NF-kB pathway, an inflammation pathway heavily associated with the progression of numerous cancers. One means of activation of the stress induced pathway is via increase pressure. As neoplasias of the brain grow within the confined space of the skull, they press against their stroma and experience higher interstitial pressure, further activating an NFkB mediated positive feedback cascade. By inhibiting the proteasome with novel imodazoline complexes, maintenance of the NFkB pathway is blocked and pressure stimulated growth should be halted. Stimulation of cultured U87 glioblastoma cells with 15mgHg for various periods of time induced a pressure activated increase in cell population, as well as activation of the NFkB pathway as well as in HEK293 embryonic kidney cells. Using our TCH-013 proteasomal inhibitor, pressure induced proliferation of these U87 cells appeared to be inhibited. Furthermore, using our TCH-01 compound pressure induced activation of the NFkB pathway was greatly in the HEK cells, indicating our imadazoline complexes target the pressure induced pathway at a downstream site enough to occlude the effect. Further screening of these compounds effects on pressure stimulated activation of NFkB and proteasomal activity is necessary in further brain cancer cell types.