Our Research

Working model: GABRA5 positive modulators

Figure 1. GABAA neurotransmitter receptor. Model of the pentameric receptor, composed of two alpha, two beta, and a gamma subunit, bound to two molecules of the GABA ligand (orange spheres) and a single molecule of a positive modulator (Benzodiazepine, Bz, the purple sphere).

Membrane transport proteins regulate movement of molecules and ions across the cell membrane, contributing to factors (such as cell volume, ionic strength, and pH) that regulate cell division and death. The importance of membrane transport proteins to cancer development and status as therapeutic 'targets' remains under investigated. My lab is interested in understanding the contribution of membrane transport proteins to development of cancers and exploring strategies to target these proteins therapeutically.

We are particularly interested in the GABAA neurotransmitter receptors, pentameric ligand-gated channels (see Figure 1). In neural cells, the GABAA receptors are fundamental to the action potential underlying brain electrical activity. Interestingly, GABAA receptor genes are expressed in pediatric and adult cancers of the central nervous system as well as cancers outside of the brain and spinal cord. We are interested in understanding: (1) the importance of the GABAA neurotransmitter receptors in disparate cancers and (2) ways to treat cancers that have functional GABAA receptors. In addition, we are involved in collaborative efforts to deliver therapeutics to solid cancers, including in the brain.

References
1. Pugh TJ, Weeraratne SD, Archer TC et al. (2012) Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations within a broad landscape of genetic heterogeneity. Nature. 488: 106-110.
2. Cho YJ, Tsherniak A, Tamayo P et al. (2011) Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. Journal Clinical Oncology. 29: 1424-1430.
3. Sengupta S, Weeraratne SD, Sun H et al. (2014) alpha5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth. Acta Neuropathol. 127: 593-603.
4. Jonas O, Calligaris D, Methuku KR et al. (2016) First in vivo testing of compounds targeting Group 3 medulloblastoma using an implantable microdevice as a new paradigm for drug development. Journal Biomedical Nanotechnology. 12: 1297-1302.
5. Sengupta S, Pomeranz Krummel D, Pomeroy S. (2017) The evolution of medulloblastoma therapy to personalized medicine. F1000Res. 6: 490.