- Assistant Professor, Department of Pediatrics - Hematology/Oncology, Committee on Cancer Biology, Committee on Immunology
PhD, Medical College of Wisconsin, Milwaukee
MD, Medical College of Wisconsin, Milwaukee
The University of Chicago
900 East 57th Street
Chicago, IL, 60637
Phone: (773) 702-6812
Dr. LaBelle's laboratory research focuses on understanding at a molecular level the reason why some pediatric cancers are resistant to therapy. He currently serves as the primary investigator on a study examining a critical network of proteins that regulate whether a malignant cell lives or dies. The normal signaling between these proteins often is disturbed in cancerous cells. Through this research, he hopes to identify novel cell death regulatory mechanisms in resistant hematopoietic malignancies and design effective strategies to overcome them. Dr. LaBelle's research is currently funded by the National Institutes of Health.
A major part of our lab focuses on using portions of the actual proteins, or peptides, as drugs and biological tools to uncover specific molecular pathways in diseased and normal cells. Peptide-based therapeutics have enormous potential for immune modulation and direct cancer treatment but have traditionally lacked efficient stabilization and delivery within patients, and thereby, have had limited clinical applications. To overcome these barriers, we are developing within the lab and through collaboration, stapled peptides and peptide amphiphiles (PAs). Stapled peptides chemically stabilize the alpha-helical secondary structure of helical peptides, protect them from proteolytic degradation, and allow for facile cellular internalization. PAs spontaneously self assemble into micelles, structures akin to those made by the detergents in your kitchen sink or washing machine, which are nanometer-sized particles that concentrate and, similar to stapled peptides, protect the therapeutic peptide from degradation while efficiently delivering the cargo to cells.
Overall, we are committed to translation of our findings to pediatric and adult patients with cancer and immune system disease. While performing research at the University of Chicago, we are in close proximity to scientists, clinicians and patients. We are deeply committed to working collaboratively with these groups to make significant inroads in treating those suffering from refractory malignancy.
1. Therapeutic targeting of BCL-2 members to reactivate cell death in tumors.
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 B cell homeostasis and its functional suppression is believed to be a key pathogenic factor in B cell lymphoma. One goal of our research is to investigate and modulate this critical, deregulated component of the apoptotic pathway in cancer cells and apply the mechanistic insights to advance a novel therapeutic strategy for reactivating cell death in treatment-refractory lymphoma.
We hypothesize that 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 restore cell death for therapeutic benefit in B cell lymphoma. Our lab applies a multidisciplinary approach and chemical collaboration to (1) test the capacity of stabilized peptides fashioned after the BIM BH3 helix to reactivate the death program in B cell lymphomas driven by distinct mechanisms of apoptotic blockade, (2) identify the explicit protein targets of these chemical tools to link cellular activity to in situ mechanism of action, and (3) determine the therapeutic potential of pharmacologic BIM BH3 replacement in mouse models of human and murine B cell lymphoma. By intertwining chemistry, lymphoma biology, and developmental therapeutics, we aim to generate fresh mechanistic insight into the pro-apoptotic potency of the BH3-only protein BIM and determine how this unique BH3 death domain can be harnessed to reactivate cell death in diverse B cell lymphomas driven by distinct and clinically relevant chemoresistance mechanisms.
2. Targeting of Regulatory T cells (Tregs) to amplify anti-tumor immune responses.
We are also interested in using peptides to target the immune system to modulate anti-tumor immune responses. Specifically, we aim to target a population of suppressive T cells called regulatory T cells (Tregs) using a helical portion of a transcription factor called FOXP3 to block the immunosuppressive ability of these specialized T cells. By doing so, we hope to lift the veil of immune protection often responsible for blocking an effective immune response against hematopoietic and solid tumors.
Additionally, using BCL-2 peptide mimetics, we aim to interrupt Treg ontogeny and maintenance in an effort to increase anti-tumor effector T cell responses. Unlike normal conventional T effector cells, Tregs rely exclusively on a narrow subset of BCL-2 proteins for survival. Therefore, we hypothesize that specific targeting of these proteins with high-fidelity peptide therapeutics will prohibit Treg-mediated immune modulation while allowing other antigen-specific T effector cell responses to occur.
3. Profiling of BCL-2 proteins during immune reconstitution following hematopoietic stem cell transplantation.
A third focus of our research is to use BCL-2 family member targeting and development of novel peptide therapeutics against immune cell targets to combat graft-versus-tumor effects and amplify anti-tumor immunotherapy after stem cell transplantation. Specifically, we aim to develop methods for high-throughput measurement of relative 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/GVHD and may allow for amplification of anti-tumor immunity in the context of tumor vaccination strategies.