Our Research Focus
The BAT lab focuses on developing novel imaging, diagnostics and therapeutic strategies for brain tumors
Our work includes:
(1) Developing the concept of metabolic biotinylation of tumor receptors to target imaging and therapeutic agents to brain tumor and to track extracellular vesicles and understand their role in gliomagenesis
(2) Engineering different secreted reporters to develop a multiplex high-throughput screening assay to find novel therapeutics against different cancer stem cells state
(3) Characterization of the naturally secreted Gaussia luciferase (Gluc) as a blood reporter for monitoring different biological processes including tumor response to therapy, viral infection, circulating stem/neuroprogenitor/T-cells
(4) Tumor-educated platelets (TEP) for pan-cancer, multi-class detection as well as biomarker discovery and their potential for longitudinal disease monitoring and response to therapy.
MULTIMODAL IMAGING IN THE CONTEXT OF CANCER
Our laboratory developed the concept of metabolic bioltinylation of mammalian cell surface receptor. By fusing a biotin acceptor peptide (BAP) to a transmembrane domain, we showed that cells in general and tumors in particular tags BAP with a single biotin on the cell surface allowing real-time tracking of cells/tumors with any imaging modalities coupled to streptavidin. This is the first report where a single reporter can be used to track cells in vivo with >5 imaging modalities including bioluminescence, fluorescence, intravital microscopy, magnetic resonance (MR), single photon emission tomography (SPECT) and positron emission tomography (PET). Working with Dr. Ralph Weissleder, we are translating this technology to in vivo applications hoping to achieve more sensitive methods for diagnosis, monitoring of brain tumors and more effective therapeutic modalities which can selectively target brain tumor cells by virtue of biotin-streptavidin system in combination with different therapies.
NOVEL GENE/CELL/DRUG THERAPY AGAINST GLIOBLASTOMA STEM CELLS
Our laboratory also focuses on high throughput screening for drugs that act specifically against brain tumor stem-like cells. We have engineered different secreted reporters which can be multiplexed together to screen for drugs that acts against three different glioma stem cells states, self renewal, differentiation and death. We have obtained some interesting drug “hits” which we are currently validating in culture as well as in our in vivo primary human invasive brain tumor models. One of our drug hits is the natural product obtusaquinone, which we found to kill glioma cells and stem cells by inducing high levels of reactive oxygen species. Working with our collaborators Dr. Ralph Mazitschek, a medicinal chemist and Dr. Wilhelm Haas, a proteomics expert, we are developing different analogues of this compound and unraveling the mechanism of action of glioma stem cells death.
In another screening project, we found that the family of cardiac glycosides, including lanatoside C, sensitizes glioma and glioma stem cells to the anti-cancer agent TRAIL. Since TRAIL does not penetrate the brain and therefore brain tumors, we explored the use of viral vectors (AAV vector) and an FDA-approved neural stem cells to deliver TRAIL to gliomas across the blood-brain barrier in combination with lanatoside C.
We have developed an in vitro model to mimic EMT-like transition in glioblastoma, namely pro-neural-to-mesenchymal transition. Using our multiplexed secreted reporters and shRNA/drug screening combined with proteomics, we are unraveling the mechanism/target that blocks this transition, leading to efficient therapeutic benefit.
MOLECULAR TUMOR BIOSENSORS
We further focus on developing molecular biosensors which reports from tumors environment. Recently, we characterized a novel luciferase from the marine copepod Gaussia princeps (Gaussia luciferase or Gluc) which is the smallest luciferase known (19.9 kDa) and much more sensitive than the ones currently in use. This luciferase is naturally secreted and therefore its expression can be monitored over time by assaying an aliquot of the conditioned medium for its activity. We showed that tumor growth and response to therapy, efficiency of gene transfer as well as stem cell survival and proliferation can be monitored in vivo by assaying few microliters of blood for the Gluc activity. Based on this secreted Gluc, we are currently developing different molecular probes which are activated strictly in the tumor environment and can be monitored both in the blood and/or localized in the animal using in vivo bioluminescence imaging.
TUMOR-EDUCATED PLATELETS IN CANCER DIAGNOSTICS AND PROGRESSION
Working with our long-time collaborator Dr. Thomas Würdinger, we showed for the first time that blood platelets carry tumor-derived biomarkers and specific gene signatures that can distinguish patients with localized and metastasized tumors from healthy individuals. We called this phenomena tumor-educated platelets or TEP. We are currently evaluating TEP for pan-cancer, multi-class detection as well as biomarker discovery and their potential for longitudinal disease monitoring and response to therapy. We are also unraveling the mechanism by which platelets are educated by the tumor and their role in cancer progression, invasion and metastasis.