Photo of Bakhos A. Tannous,  PhD

Bakhos A. Tannous, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 726-6026
Fax: (617) 724-1537


btannous@hms.harvard.edu

Bakhos A. Tannous, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Associate Professor, Neurology, Harvard Medical School
  • Associate Neuroscientist, Neurology, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Glioblastoma tumors are highly heterogeneous and there is a complex interaction among different types of tumor cells and stromal cells within the tumor. Recently it has been shown that the majority of tumor cells do not have the capacity to recapitulate a phenocopy of the original tumor and that only a small subpopulation of cells in the tumor, called cancer stem cells, have that ability upon xenotransplantation in nude mice. These cancer stem cells appear to be more resistant to conventional therapy (chemotherapy and radiation) as compared to the non-cancer stem cells. Following current therapy for high-grade glioma tumors, most patients die within a year from a new secondary tumor foci forming within one centimeter of the resected area. These foci are enriched for cancer stem cells, and it is likely that they are responsible for tumor recurrence. One aspect of our work is to develop novel bioluminescent reporter systems to monitor self-renewal, differentiation or death of GBM stem cells simultaneously and use these reporters to screen for drugs which can increase therapeutic efficacy for GBM stem cells by either: (1) eradicating these cells or (2) revert GBM stem cells into a more differentiated state which can then response to conventional therapies.

Another aspect of our research is to target brain tumors using different gene transfer technologies. In collaboration with Dr. Ralph Weissleder, we have engineered a reporter protein which is metabolically biotinylated and selectively presents biotin on the tumor cell surface. This reporter allows sensitive imaging of glioma cells expressing it using labeled streptavidin moieties and different imaging modalities, such as positron emission tomography and magnetic resonance. We are currently extending this work and developing a gene delivery system that can change the surface of a GBM cell so that it presents a molecular “beacon” (biotinylated receptors) to attract diagnostic and therapeutic agents to it. This strategy is designed to make tumor cells a selective, “easy target” for different biotinylated-imaging agents (for diagnostics) or biotinylated-toxins (for therapy) complexed to streptavidin which binds with extremely high affinity to biotin (Kd = 10-15) and can be internalized into tumor cells. A critical component of our strategy is to facilitate delivery of these biotinylated therapeutic/diagnostic agents from the vasculature into gliomas by targeting endothelial cells lining the blood vessels in the brain which normally facilitate passage of molecules across the blood-brain barrier.

Since the last decade, a largely secluded source of gene expression data has accumulated, and is publicly available, comparing human cancer samples with normal tissue. This encouraged us to develop a strategy to order glioblastoma gene families by level and frequency of overexpression in order to identify putative treatment targets in the glioblastoma kinase gene family. In collaboration with Dr. Wurdinger at the VU Medical Center, the Netherlands, we identified a GBM-specific kinase expression profile that suggests signal transduction pathways to be involved in gliomagenesis. Out of the identified glioblastoma-specific overexpressed kinases, we selected WEE1 kinase as a putative treatment target based on its potential function as a mitotic gatekeeper and its specific overexpression in GBM. We showed that GBM tumors are treated efficiently upon inhibition of WEE1 kinase using a drug or small interfering RNAs (siRNAs) in combination with conventional therapy. We are currently working on identify the role of WEE1 tyrosine kinase as well as different members of the TP53 pathway mutated in over 80% of GBM and known to affect WEE1 inhibition activity.

Pre-clinical analysis of any diagnostic/therapeutic strategy using clinically relevant animal models is very important for translational research. We use primary GBM stem-like cells dissociated from patient tissue sections and cultured as neural spheres which recapitulate a phenocopy of the patient tumor with infiltrating/migrating capability upon sterotactic injection in the brain of nude mice.

 

Publications

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  • Wong HK, Fatimy RE, Onodera C, Wei Z, Yi M, Mohan A, Gowrisankaran S, Karmali P, Marcusson E, Wakimoto H, Stephens R, Uhlmann EJ, Song JS, Tannous B, Krichevsky AM. TCGA analysis predicts microRNA for targeting cancer growth and vascularization in glioblastoma. Mol Ther 2015. PubMed
  • Balaj L, Atai NA, Chen W, Mu D, Tannous BA, Breakefield XO, Skog J, Maguire CA. Heparin affinity purification of extracellular vesicles. Sci Rep 2015; 5:10266. PubMed
  • Lai CP, Kim EY, Badr CE, Weissleder R, Mempel TR, Tannous BA, Breakefield XO. Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters. Nat Commun 2015; 6:7029. PubMed
  • Teng J, Hejazi S, Badr CE, Tannous BA. Systemic anticancer neural stem cells in combination with a cardiac glycoside for glioblastoma therapy. Stem Cells 2014. PubMed
  • Hiddingh L, Tannous BA, Teng J, Tops B, Jeuken J, Hulleman E, Boots-Sprenger SH, Vandertop WP, Noske DP, Kaspers GJ, Wesseling P, Wurdinger T. EFEMP1 induces 粒-secretase/Notch-mediated temozolomide resistance in glioblastoma. 2014; 5:363-74. PubMed
  • Lai CP, Mardini O, Ericsson M, Prabhakar S, Maguire CA, Chen JW, Tannous BA, Breakefield XO. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano 2014; 8:483-94. PubMed
  • van der Mijn JC, Sol N, Mellema W, Jimenez CR, Piersma SR, Dekker H, Schutte LM, Smit EF, Broxterman HJ, Skog J, Tannous BA, Wurdinger T, Verheul HM. Analysis of AKT and ERK1/2 protein kinases in extracellular vesicles isolated from blood of patients with cancer. J Extracell Vesicles 2014; 3:25657. PubMed
  • Elman JS, Murray RM, Wang F, Shen K, Gao S, Conway KE, Yarmush ML, Tannous BA, Weissleder R, Parekkadan B. Pharmacokinetics of natural and engineered secreted factors delivered by mesenchymal stromal cells. PLoS ONE 2014; 9:e89882. PubMed
  • Lai CP, Tannous BA, Breakefield XO. Noninvasive in vivo monitoring of extracellular vesicles. Methods Mol Biol 2013; 1098:249-58. PubMed
  • Lewandrowski GK, Magee CN, Mounayar M, Tannous BA, Azzi J. Simultaneous in vivo monitoring of regulatory and effector T lymphocytes using secreted Gaussia luciferase, Firefly luciferase, and secreted alkaline phosphatase. Methods Mol Biol 2013; 1098:211-27. PubMed
  • Bovenberg MS, Degeling MH, Hejazi S, Amante RJ, van Keulen M, Jeuken JW, Akbaripanahi S, Vleggeert-Lankamp CL, Tannous M, Wesseling P, Wurdinger T, Tannous BA. Multiplex blood reporters for simultaneous monitoring of cellular processes. Anal Chem 2013; 85:10205-10. PubMed
  • Tannous BA, Kerami M, Van der Stoop PM, Kwiatkowski N, Wang J, Zhou W, Kessler AF, Lewandrowski G, Hiddingh L, Sol N, Lagerweij T, Wedekind L, Niers JM, Barazas M, Nilsson RJ, Geerts D, De Witt Hamer PC, Hagemann C, Vandertop WP, Van Tellingen O, Noske DP, Gray NS, Würdinger T. Effects of the selective MPS1 inhibitor MPS1-IN-3 on glioblastoma sensitivity to antimitotic drugs. Journal of the National Cancer Institute 2013; 105:1322-31. PubMed
  • Bovenberg MS, Degeling MH, Tannous BA. Cell-based Immunotherapy Against Gliomas: From Bench to Bedside. Mol Ther 2013. PubMed
  • Bovenberg MS, Degeling MH, Tannous BA. Advances in stem cell therapy against gliomas. Trends Mol Med 2013. PubMed
  • Badr CE, Van Hoppe S, Dumbuya H, Tjon-Kon-Fat LA, Tannous BA. Targeting Cancer Cells With the Natural Compound Obtusaquinone. Journal of the National Cancer Institute 2013. PubMed
  • Maguire CA, Bovenberg MS, Crommentuijn MH, Niers JM, Kerami M, Teng J, Sena-Esteves M, Badr CE, Tannous BA. Triple bioluminescence imaging for in vivo monitoring of cellular processes. Mol Ther Nucleic Acids 2013; 2:e99. PubMed
  • van Rijn S, Nilsson J, Noske DP, Vandertop WP, Tannous BA, Würdinger T. Functional multiplex reporter assay using tagged Gaussia luciferase. Sci Rep 2013; 3:1046. PubMed
  • Kodack DP, Chung E, Yamashita H, Incio J, Duyverman AM, Song Y, Farrar CT, Huang Y, Ager E, Kamoun W, Goel S, Snuderl M, Lussiez A, Hiddingh L, Mahmood S, Tannous BA, Eichler AF, Fukumura D, Engelman JA, Jain RK. Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc Natl Acad Sci U S A 2012; 109:E3119-27. PubMed
  • Niers JM, Chen JW, Lewandrowski G, Kerami M, Garanger E, Wojtkiewicz G, Waterman P, Keliher E, Weissleder R, Tannous BA. Single reporter for targeted multimodal in vivo imaging. J Am Chem Soc 2012; 134:5149-56. PubMed
  • Tannous BA, Teng J. Secreted blood reporters: Insights and applications. Biotechnol Adv 2011; 29:997-1003. PubMed
  • Badr CE, Tannous BA. Bioluminescence imaging: progress and applications. Trends Biotechnol 2011. PubMed
  • Badr CE, Wurdinger T, Nilsson J, Niers JM, Whalen M, Degterev A, Tannous BA. Lanatoside C sensitizes glioblastoma cells to tumor necrosis factor-related apoptosis-inducing ligand and induces an alternative cell death pathway. 2011. PubMed
  • Niers JM, Kerami M, Pike L, Lewandrowski G, Tannous BA. Multimodal In Vivo Imaging and Blood Monitoring of Intrinsic and Extrinsic Apoptosis. Mol Ther 2011. PubMed
  • Niers JM, Chen JW, Weissleder R, Tannous BA. Enhanced in vivo imaging of metabolically biotinylated cell surface reporters. Anal Chem 2011; 83:994-9. PubMed
  • Smits M, Mir SE, Nilsson RJ, van der Stoop PM, Niers JM, Marquez VE, Cloos J, Breakefield XO, Krichevsky AM, Noske DP, Tannous BA, Würdinger T. Down-regulation of miR-101 in endothelial cells promotes blood vessel formation through reduced repression of EZH2. PLoS ONE 2011; 6:e16282. PubMed
  • Badr CE, Wurdinger T, Tannous BA. Functional Drug Screening Assay Reveals Potential Glioma Therapeutics. 2010. PubMed
  • Smits M, Nilsson J, Mir SE, van der Stoop PM, Hulleman E, Niers JM, de Witt Hamer PC, Marquez VE, Cloos J, Krichevsky AM, Noske DP, Tannous BA, Würdinger T. miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. 2011; 1:710-20. PubMed
  • Mir SE, De Witt Hamer PC, Krawczyk PM, Balaj L, Claes A, Niers JM, Van Tilborg AA, Zwinderman AH, Geerts D, Kaspers GJ, Peter Vandertop W, Cloos J, Tannous BA, Wesseling P, Aten JA, Noske DP, Van Noorden CJ, Würdinger T. In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma. Cancer Cell 2010; 18:244-57. PubMed
  • Prabhakar S, Brenner GJ, Sung B, Messerli SM, Mao J, Sena-Esteves M, Stemmer-Rachamimov A, Tannous B, Breakefield XO. Imaging and therapy of experimental schwannomas using HSV amplicon vector-encoding apoptotic protein under Schwann cell promoter. Cancer Gene Ther 2010; 17:266-74. PubMed
  • Sharma R, Tsuchiya M, Skobe Z, Tannous BA, Bartlett JD. The acid test of fluoride: how pH modulates toxicity. PLoS ONE 2010; 5:e10895. PubMed
  • Saydam O, Shen Y, Würdinger T, Senol O, Boke E, James MF, Tannous BA, Stemmer-Rachamimov AO, Yi M, Stephens RM, Fraefel C, Gusella JF, Krichevsky AM, Breakefield XO. Downregulated microRNA-200a in meningiomas promotes tumor growth by reducing E-cadherin and activating the Wnt/beta-catenin signaling pathway. Mol Cell Biol 2009; 29:5923-40. PubMed
  • Maguire CA, Deliolanis NC, Pike L, Niers JM, Tjon-Kon-Fat LA, Sena-Esteves M, Tannous BA. Gaussia luciferase variant for high-throughput functional screening applications. Anal Chem 2010; 81:7102-6. PubMed
  • Tannous BA,Christensen AP,Pike L,Wurdinger T,Perry KF,Saydam O,Jacobs AH,Garcia-Anoveros J,Weissleder R,Sena-Esteves M,Corey DP,Breakefield XO. Mutant sodium channel for tumor therapy. Mol Ther 2009; 17:810-9. PubMed
  • Würdinger T, Tannous BA. Glioma angiogenesis: Towards novel RNA therapeutics. Cell Adh Migr 2009; 3:230-5. PubMed
  • Tannous B, Lee-Lewandrowski E, Sharples C, Brugge W, Bigatello L, Thompson T, Benzer T, Lewandrowski K. Comparison of conventional guaiac to four immunochemical methods for fecal occult blood testing: implications for clinical practice in hospital and outpatient settings. Clin Chim Acta 2009; 400:120-2. PubMed
  • van Vuurden DG, Yazdani M, Bosma I, Broekhuizen AJ, Postma TJ, Heimans JJ, van der Valk P, Aronica E, Tannous BA, Würdinger T, Kaspers GJ, Cloos J. Attenuated AMPA receptor expression allows glioblastoma cell survival in glutamate-rich environment. PLoS ONE 2009; 4:e5953. PubMed
  • Tannous BA. Gaussia luciferase reporter assay for monitoring biological processes in culture and in vivo. Nat Protoc 2009; 4:582-91. PubMed
  • Chung E, Yamashita H, Au P, Tannous BA, Fukumura D, Jain RK. Secreted Gaussia luciferase as a biomarker for monitoring tumor progression and treatment response of systemic metastases. PLoS ONE 2009; 4:e8316. PubMed
  • Wurdinger T,Tannous BA,Saydam O,Skog J,Grau S,Soutschek J,Weissleder R,Breakefield XO,Krichevsky AM. miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells. Cancer Cell 2008; 14:382-93. PubMed
  • Deliolanis NC,Kasmieh R,Wurdinger T,Tannous BA,Shah K,Ntziachristos V. Performance of the red-shifted fluorescent proteins in deep-tissue molecular imaging applications. J Biomed Opt 2008; 13:044008. PubMed
  • Hewett JW, Nery FC, Niland B, Ge P, Tan P, Hadwiger P, Tannous BA, Sah DW, Breakefield XO. siRNA knock-down of mutant torsinA restores processing through secretory pathway in DYT1 dystonia cells. Hum Mol Genet 2008; 17:1436-45. PubMed
  • Lewandrowski K, Flood J, Finn C, Tannous B, Farris AB, Benzer TI, Lee-Lewandrowski E. Implementation of point-of-care rapid urine testing for drugs of abuse in the emergency department of an academic medical center: impact on test utilization and ED length of stay. Am J Clin Pathol 2008; 129:796-801. PubMed
  • Wurdinger T,Badr C,Pike L,de Kleine R,Weissleder R,Breakefield XO,Tannous BA. A secreted luciferase for ex vivo monitoring of in vivo processes. Nat Methods 2008; 5:171-3. PubMed
  • Hewett JW, Tannous B, Niland BP, Nery FC, Zeng J, Li Y, Breakefield XO. Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cells. Proc Natl Acad Sci U S A 2007; 104:7271-6. PubMed
  • Badr CE, Hewett JW, Breakefield XO, Tannous BA. A highly sensitive assay for monitoring the secretory pathway and ER stress. PLoS ONE 2007; 2:e571. PubMed
  • Tannous BA, Grimm J, Perry KF, Chen JW, Weissleder R, Breakefield XO. Metabolic biotinylation of cell surface receptors for in vivo imaging. Nat Methods 2006; 3:391-6. PubMed
  • Tannous BA, Kim DE, Fernandez JL, Weissleder R, Breakefield XO. Codon-optimized Gaussia luciferase cDNA for mammalian gene expression in culture and in vivo. Mol Ther 2005; 11:435-43. PubMed
  • Lee-Lewandrowski E, Januzzi JL, Green SM, Tannous B, Wu AH, Smith A, Wong A, Murakami MM, Kaczmarek J, Apple FS, Miller WL, Hartman K, Jaffe AS. Multi-center validation of the Response Biomedical Corporation RAMP NT-proBNP assay with comparison to the Roche Diagnostics GmbH Elecsys proBNP assay. Clin Chim Acta 2007; 386:20-4. PubMed
  • Badr CE, Niers JM, Tjon-Kon-Fat LA, Noske DP, Wurdinger T, Tannous BA. Real-time monitoring of nuclear factor kappaB activity in cultured cells and in animal models. Mol Imaging 2009; 8:278-90. PubMed
  • Deliolanis NC, Dunham J, Wurdinger T, Figueiredo JL, Bakhos T, Ntziachristos V. In-vivo imaging of murine tumors using complete-angle projection fluorescence molecular tomography. J Biomed Opt 2009; 14:030509. PubMed
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