Therapeutic targeting of BCL-2 members to reactivate cell death in tumors and modulate the immune system
The BCL-2 family comprises an essential network of proteins that govern the cell’s decision to live or die. BIM, a pro-apoptotic BH3-only protein of the BCL-2 family is a master regulator of immune cell homeostasis and its functional suppression is believed to be a key pathogenic factor in normal immune cell homeostasis and the evolution of hematopoietic malignancies. One overarching goal of our research is to investigate and modulate BIM’s apoptotic governance and apply mechanistic insights to advance a novel therapeutic strategies for reactivating cell death in treatment-refractory malignancies.
The potency of BIM BH3 in triggering cell death reflects its capacity to engage a diversity of key protein targets and death pathways, and that pharmacologic replacement of BIM’s “death domain” using stabilized peptides will induce cell death for therapeutic benefit. Our lab applies a multidisciplinary approach and chemical collaboration to (1) test the capacity of BCL-2-small-molecule mimetics and peptides fashioned after the BIM BH3 helix to reactivate the death program in malignancies driven by distinct mechanisms of apoptotic blockade, (2) identify the explicit protein targets of these chemical tools to link cellular activity to in situmechanism of action, and (3) determine the non-apoptotic effects of BCL-2 family targeting in malignant cells. By intertwining chemistry, oncology, immunology, and developmental therapeutics, we aim to generate fresh mechanistic insight into BCL-2 family targeting and determine how unique BH3 death domains can be harnessed to reactivate cell death in cells driven by distinct and clinically relevant apoptotic resistance and mechanisms.
Additionally, using BCL-2 peptide mimetics, we aim to modulate T cell populations in an effort to increase anti-tumor effector T cell responses. T cells rely on different subsets of BCL-2 proteins for ontogeny, survival, and expansion during their lifetime. Therefore, we hypothesize that specific targeting of these proteins with high-fidelity peptide and small molecule therapeutics will allow for controlled immune modulation that can be used for therapeutic benefit. Examples of this are manipulation of chimeric antigen receptor (CAR) T cells and of adoptively transferred human regulatory T cells.
Profiling and drugging BCL-2 proteins during immune reconstitution following hematopoietic stem cell transplantation
A translational focus of our research is to use BCL-2 family member targeting against immune cell targets to combat graft-versus-host disease (GVHD) and amplify anti-tumor immunotherapy following stem cell transplantation. We are developing methods for high-throughput measurement of BCL-2 family member expression patterns in different lymphocyte subsets in an effort to define explicit targets for immune regulation. We believe that the advent of small molecule and peptide modulators of BCL-2 family members makes therapeutic targeting of immune subsets achievable in patients with autoimmune diseases/GVHD and may allow for amplification of anti-tumor immunity in the context of tumor vaccination strategies.
Peptide-based therapeutic targeting and in vivo trafficking
In collaboration with the Matthew Tirrell, PhD of the Institute for Molecular Engineering at that University of Chicago, we are designing and studying the intracellular trafficking patterns of self-assembling peptide therapeutics. Our goal is to manipulate these promising peptide delivery systems to target protein:protein interactions within diseased and normal cells. We utilize fluorescence resonance energy transfer (FRET) and super resolution confocal microscopy to better understand intracellular trafficking patterns in real time. We are also working on specifically targeting our treatments to diseased cells through the internalization of therapeutic peptides designed to reactivate cell death and modulate cell signaling pathways.