BOOHAKER
LABORATORY

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Research Focus

The major interest of the lab is understanding the mechanisms of immune activation and regulation. Specifically, we are focusing on understanding and overcoming the mechanisms of T-cell exhaustion in the face of immune checkpoint signals in cancer progression. The merging of oncology with immunology is a promising combination of disciplines to uncover novel therapeutic avenues for combating numerous tumor types. Our lab utilizes an interdisciplinary approach in the design and evaluation of immune checkpoint inhibitors that includes, but is not limited to, the following: cell-free determination of protein-protein interactions, rational design of peptides and small molecules, nano-particle delivery systems, and classical flow-cytometric methods of assessing immune population phenotypic changes.

Targeting of the Programmed Cell Death-1 receptor (PD-1)/PD-1 Ligand checkpoint interaction as a means to overcome tumor-induced immune evasion.

Currently the major focus of the lab is targeting of the Programmed Cell Death-1 receptor (PD-1)/PD-1 Ligand checkpoint interaction as a means to overcome tumor-induced immune evasion. Immune evasion, resulting from tumor-induced expression of checkpoint ligands that effectively turn off immune surveillance towards cancerous cells, plays an appreciable role in tumor cell survival.

This otherwise protective mechanism counters auto-immunity through rigorous selection of T-cells through central and peripheral tolerance mechanisms, thus promoting T-cell exhaustion. Components of peripheral tolerance, including surface proteins and their ligands, such as PD-1 and PD-L1, are necessary to regulate immunity. Immune surveillance is rendered ineffective when the tumor environment overwhelms the cytotoxic arm of the adaptive immune system with chronic antigen (PD-L1) exposure leading to a state of ‘exhaustion’ or anergy of antigen-specific T-cells.

Immune Evasion: tumor cells in pink in the center and the incorporated yellow and green antigen presenting cells (APCs). The aqua ligands emanating from the center cells represent PD-L1. The yellow receptors attached to the various cells around the center cells represent PD-1. J Clin Invest. 2015 Sep; 125(9):3384-91. doi: 10.1172/JCI180011

Immune Evasion: tumor cells in pink in the center and the incorporated yellow and green antigen presenting cells (APCs). The aqua ligands emanating from the center cells represent PD-L1. The yellow receptors attached to the various cells around the center cells represent PD-1.
J Clin Invest. 2015 Sep; 125(9):3384-91. doi: 10.1172/JCI180011

A large proportion of tumor-infiltrating lymphocytes (TILs), which have the ability to secrete cytotoxic proteins, express PD-1 and PD-L1, both of which are upregulated in a number of cancers. These occurrences, along with the adverse outcomes associated with high PD-L1 expression levels, make PD-1 blockade an attractive target for therapeutic manipulation.

This laboratory uses computational modeling and binding assays to map binding domains of surface receptors to design targeted small molecule inhibitors. This approach is applied to the effort of this laboratory to target inhibition of the PD-1/PD-L1 checkpoint interaction.

Computational modeling and binding assays direct the design and evaluation of peptide based inhibitors.

Computational modeling and binding assays direct the design and evaluation of peptide based inhibitors.

 

 

 

 

 

 

 

 

 

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Rebecca Boohaker, Ph.D

Associate Research Biologist, Oncology Department

Rebecca Boohaker joined Southern Research in 2013 to complete her postdoctoral fellowship. In 2016, she became an associate research biologist in the Oncology Department of the Drug Discovery division. She is currently interested in investigating the processes by which cancer cells exploit their own regulatory machinery to promote tumorigenesis as means to develop novel therapeutics. [ Read Full Bio Here ]



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