LOS ANGELES, CA--(Marketwire - Sep 25, 2012) - Gliomablastoma multiform (GBM) is the most fatal form of all brain cancers in humans. Response to current therapies remains extremely poor, with dismal survival statistics. Recently, calpains, a large conserved family of cysteine proteases regulated by calcium, have been implicated in GBM tumor pathogenesis. Calpain activity is implicated in several physiological processes, including cytoskeletal remodeling, cellular signaling and apoptosis. The calpain isoforms, calpain1 and calpain2, are ubiquitous and abundant in the central nervous system (CNS).

Calpain 2 has been found to be critical for GBM cell invasion in vitro. Both calpain 1 and calpain 2 were also found to play distinct roles in GBM neurosphere proliferation. The precise molecular mechanisms underlying these calpain-mediated processes however remain an enigma. Recently another calpain isoform, calpain10, was identified in GBM, specifically in the mitochondrial intermembrane space, but its function in GBM and GBM metabolism also remains unknown. Given the implication in the processes crucial for GBM development and progression, calpains are currently considered as potential therapeutic targets. However, calpain targeting drugs could interfere with ubiquitous calpains present in healthy neurons and interfere with anti-cancer treatments, as calpains also play crucial roles in chemotherapy-induced apoptosis.

Therefore, we propose to (1) determine the role of the neuronal calpain system (calpain 1, calpain 2, calpain10) in the regulation of GBM tumorgenesis, tumor heterogeneity and metastasis (2) elucidate the function of the neuronal calpain system in GBM and GBM neurosphere metabolism and bioenergetics and (3) develop a GBM-specific targeting peptide to deliver isoform specific calpain siRNA in vivo. We also propose to generate fluorescence-based biosensors to monitor calpain activation both in single cells and in real time. These studies will ultimately advance our understanding of the cellular mechanisms regulating GBM tumor pathogenesis and provide new tools to both better understand the roles of neuronal calpains and to target neuronal calpains in the brain.

This work will be conducted by Dr. Sohila Zadran. Dr. Zadran is a bioengineer and a neuroscientist. Dr. Zadran has already successfully engineered a fluorescence resonance energy transfer (FRET)-based single cell biosensor to monitor calpain activity in neurons on a single cell level and in real time. Dr. Zadran has also developed a rabies-virus glycoprotein (RVG) construct capable of delivering isoform specific calpain siRNAs to the brain. Recently, Dr. Zadran constructed an enhanced acceptor fluorescence (EAF)-based biosensor to monitor ATP flux in single GBM cells and GBM neurospheres in real time.

About Dr. Sohila Zadran: Dr. Zadran completed her undergraduate studies at the University of California, Berkeley in Molecular Cell Biology, with an emphasis in Neurobiology (2004-2007). She then received her doctoral degree at the University of Southern California in Neuroscience, with an emphasis in Neural Engineering (2007-2010). She completed her post-doctoral training at the California Institute of Technology (2010-2011) in the Division of Biology, with an Emphasis in Systems Neuroscience.

She is currently the founder and CSO of Lillium Industries, LLC and the co-founder and owner of Agarionan Pharmaceuticals. Dr. Zadran currently resides in Los Angeles, California, USA.