Badr Lab

Overview

Glioma, a common form of primary central nervous system tumor, is an aggressive, incurable type of brain tumor. This heterogeneous tumor population is enriched in a subset of brain-tumor initiating cells or glioma stem cells (GSCs) with self-renewal and tumor initiation capacities.

Our group is focused on studying the major genetic hubs driving this cancer subpopulation and the molecular aspects governing self-renewal and tumor initiation. In our studies we use a multidisciplinary approach combining targeted chemical and genetic inhibitors as well as protein profiling to interrogate GSCs and develop novel therapies for brain tumors.

Using this approach, we have identified metabolic dependencies in highly aggressive GSCs which can be exploited to specifically target these cells. We are also interested in studying tumor plasticity, in particular the ability of GSCs to change their transcriptional profile in response to different environmental or therapeutic insults, thereby favoring a more aggressive and resistant tumor population.
 
While the incidence of primary brain tumors is relatively low, about one third of all extracranial cancer patients develop brain metastases (BM), a significant cause of patient morbidity and mortality. We are also studying various mechanisms of cancer metastasis to the brain.

These studies could help us understand the mechanism of cancer brain tropism to prevent brain metastasis and increase survival in cancer patients.

Research Projects

Understanding plasticity, inherent heterogeneity and “survival queues” in Gliomas

• Developing in vitro models and reporters to study cellular dynamics in Glioma Stem Cells
• Genome-wide gain-of-function Genetic screens and targeted inhibitors to identify genetic modulators of Glioma stem cells

Transcriptional profiles and genetic signatures of brain tumor cells define the major glioblastoma subtypes and can be used to guide prognosis. The mesenchymal subset for example, is generally associated with resistance to current therapies and a poor prognosis.

Recent evidence indicates plasticity between GSCs subtypes where GCSs can undergo differentiation into a more aggressive subtype through intrinsic activation of various transcription factors. In a recent study, we have identified a subpopulation of glioblastoma stem cells that escape differentiation. These cells possess a stem-like signature with prominent mesenchymal features.

They tend to be more aggressive when implanted into the brain of nude mice as compared to their parental GSCs line and have a superior resistance to radiation and therapy. Our findings endorse cellular plasticity and intratumor heterogeneity in glioblastoma.

We are developing different in vitro models and performing genome-scale genetic screening to identify different genes that control the GSCs fate. This work could have direct therapeutic implications by blocking the rise of aggressive GBM phenotypes or reverting the latter into a clinically-manageable tumor type.

Identifying vulnerabilities and new genetic targets: Developing targeted therapeutics

Identifying vulnerabilities and dependencies in primary cancer cells might be key to overcoming resistance and tumor recurrence in patients. Our lab is working towards the identification of new therapeutic targets that could be exploited to treat brain tumors and other cancer types.

Ubiquitin ligase complex role in GBM and breast cancer

The ubiquitin-proteasome system controls many aspects of cell regulation and homeostasis through ubiquitination and degradation of substrate proteins. Various components of the ubiquitin proteasome are dysregulated in human diseases including cancer. We have identified one such complex that plays a key role in gliomas and breast cancer. Disruption of this complex leads to cancer cell death. We are currently exploring different strategies to develop therapeutics targeting this ubiquitin ligase complex.

A: We identified a ubiquitin ligase essential for GBM and GSCs survival and proliferation through the activation of AKT and other unknown mechanisms.

B: Our therapeutic strategy consists on blocking the assembly of the different components of this ubiquitin ligase complex using small molecules which disrupts its ubiquitin ligase activity and results in cancer cells death.

Targeting metabolic vulnerabilities in cancer (Reactive Oxygen Species, lipid metabolism)

Using targeted inhibitors and genetic profiling of different primary GBM tumor cells and GSCs subtypes, we noted a marked increase in different metabolic pathways and identified key enzymes responsible for maintaining tumor progression and cell proliferation. We are testing different targeted inhibitors of these key enzymes to block different metabolic pathways essential for tumor growth using in vitro as well as orthotopic brain tumor models in mice.

Exploring alternative strategies to deliver therapeutics to the brain (Intranasal delivery; gene therapy)

In an effort to improve drug delivery to brain tumors and minimize systemic toxicity, we are exploring different strategies to deliver therapeutics to the brain. We are working towards delivery strategies such as intranasal delivery with the following advantages:

• They are non-invasive and could be easily applied by the patient
• They permit rapid and efficient delivery of small and large molecules directly to the brain
• They are able to bypass the Blood-Brain-Barrier
• They could reduce severe systemic toxicity
• They are cost-effective since a lower concentration of drugs is needed due to site-specific delivery.

Brain tumor metastasis are particularly lethal and hard to treat. Understanding the mechanism of cancer brain tropism could help prevent brain metastasis and increase survival in cancer patients. We are working on generating breast cancer brain metastasis models and using them for in vivo genetic screens to identify genes that control brain tropism of breast cancer cells.

Research Positions

We are continuously seeking highly motivated and talented individuals to join our research team. We welcome applicants at different levels of training/education (undergraduate, graduate and medical students, Residents and Fellows). Interested individuals should send a curriculum vitae to Dr. Christian E. Badr at badr.christian@mgh.harvard.edu.

Read about and apply for residency, fellowship and observership programs in neurology. 

All applicants should register with the Mass General Careers website.

Publications

Volak A, LeRoy S, Natasan JS, Park D., Cheah PS, Maus A, Fitzpatrick Z, Hudry E, Pinkham K, Gandhi S, Hyman BT, Mu D, GuhaSarkar D, Stemmer-Rachamimov AO, Sena-Esteves M, Badr CE#, Maguire C.A#, Virus vector-mediated genetic modification of brain tumor stromal cells after intravenous delivery, J Neuro-Oncology 2018
# co-senior authors

Teng J*, da Hora CC*, Kantar RS, Nakano I, Wakimoto H, Batchelor T, Chiocca EA, Badr CE#, Tannous BA#. Dissecting Inherent Heterogeneity in patient-derived glioblastoma culture models. Neuro-Oncology 2016. * # Equal contribution

Crommentuijn MH, Maguire CA, Niers JM, Vandertop WP, Badr CE, Würdinger T, Tannous BA. Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse model of invasive glioblastoma. Mol Oncol 2015.

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.

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.

Amante RJ, Badr CE. Cell-based bioluminescence screening assays. Methods Mol Biol 2013; 1098:185-95.

Badr CE. Bioluminescence imaging: basics and practical limitations. Methods Mol Biol 2013; 1098:1-18.

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.

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.

Badr CE, Tannous BA. Bioluminescence imaging: progress and applications. Trends Biotechnol 2011.

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.

Badr CE, Wurdinger T, Tannous BA. Functional Drug Screening Assay Reveals Potential Glioma Therapeutics. 2010.

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.