The Tannous lab focuses on developing novel imaging and therapeutic strategies for brain tumors. Their recent work includes characterization of the naturally secreted Gaussia luciferase (Gluc) as a blood reporter for monitoring different biological processes including tumor growth and response to therapy, viral infection and propagation, as well as viability of circulating stem/neuroprogenitor cells and T-lymphocytes. They have used Gluc to develop a high-throughput screening assay to find novel therapeutics against glioblastoma. They are currently applying this assay to screen for modulators of the cancer stem cells subpopulation of brain tumors. The Tannous lab also developed the concept of metabolic biotinylation of tumor receptors using gene transfer and used this technology to target imaging and therapeutic agents to glioblastoma. They are actively involved in combing these technologies to achieve novel combined drug/gene therapies for glioblastoma in general and cancer stem cells in particular.
Neuroscience Center at Massachusetts General Hospital
Massachusetts General Hospital – East
Building 149, 13th Street
Charlestown, MA 02129
Bakhos A. Tannous, PhD
Alumni Group Members
Molecular Tumor Biosensors
|Targeting tumors with biotin||Neuroprogenitor cells
The Tannous laboratory focuses 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.
Gene Transfer Technologies for Tumors
Another aspect of Dr. Tannous’ research is to target brain tumors using different gene transfer technologies. We have engineered a by endogenous mammalian biotin ligase and presents biotin on the tumor cell surface. This reporter allows for non-invasive real time imaging of any cell type transduced to express it in culture or in vivo with labeled streptavidin moieties and different imaging modalities including fluorescence molecular tomography (FMT), positron emission tomography (PET) and magnetic resonance (MR). Currently, 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.
High-Throughput Screening Assays
Our laboratory also focuses on high throughput screening for drugs which act specifically against brain tumor stem-like cells. Based on the naturally secreted Gluc, we have developed a . 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. We have also showed that Gluc secretion can be used as a marker for protein secretion as well as endoplasmic reticulum (ER)-stress, a hallmark of many neurological disorders. We found that human fibroblasts from Parkinson as well as Dystonia patients have a defect in processing of Gluc and are much more sensitive to ER-stress as compared to normal fibroblasts. We are currently screening for drugs which restore protein processing and/or alleviate the ER stress in these patient cells.
Working with Dr. Thomas Wurdinger and using open access available data and in silico analysis, we found that several kinases, including WEE1 tyrosine kinase and monopolar spindle 1 (MPS1) kinase, are highly upreguated in glioblatomas. We are currently validating these kinases as potential therapeutic targets for glioblastoma in combination with conventional therapies using different intracranial animal models, which infiltrates the brain of mice similar to human tumors.
Muscular Dystrophy Cell Lines
July 2011: This project is currently in Partners IRB and RVL review and if approved will be conducted in collaboration with Brian Tseng, MD, (formerly of MGH Neurology) with support pledged by Ryan's Quest foundation. It is our hope to help move the DMD field forward by developing a human muscular dystrophy immortalized cell line, and promote testing by any qualified investigator with emerging screening tools using FDA-approved drugs (for other indications), novel compounds and nutraceuticals to slow the process of muscular dystrophy and perhaps enhance strength. Such human muscular dystrophy cell lines will enable better understanding of the pathogenesis of muscular dystrophy and potential targets to intervene in favorable ways.
Duchenne Muscular Dystrophy (DMD) is the most common and lethal muscular dystrophy. One in 3,500 live-born males will have DMD and there are estimates of over 15,000 boys in the USA. Boys with DMD tend to lose the ability to walk by 10-12 years of age when they become wheelchair dependent and generally do not survive beyond their teens due to cardiorespiratory compromise.
Although the gene for DMD has been identified, there is still limited understanding about overall muscular dystrophy pathogenesis, much less specific treatments or cures for any muscular dystrophy. There are gene therapy and molecular medicines on the horizon but none have yet emerged as clinically efficacious for humans nor FDA approved. One major shortcoming in the muscular dystrophy research field is a lack of a publically-available immortalized human cell line from a human Duchenne muscular dystrophy patient.
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NCBI PubMed Publications (Tannous, BA)
NCBI PubMed Publications (Tannous, B)
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