Characterization of MALT1 Inhibitors and Their Effect on Leukemic Cell Growth Properties

Author(s)

Christina Snyder, Rowan University

Date Approved

2017

Document Type

Thesis

Degree Name

Master of Science in Molecular Pathology and Immunology

Department

Molecular Biology

College

Graduate School of Biomedical Sciences

Sponsor

Venenum Biodesign, LLC and Oncoveda, of Genesis Biotechnology Group

First Advisor

Salvatore Caradonna, PhD

Committee Member 1

Jason Trama, PhD

Committee Member 2

Joseph T. Nickels, PhD

Committee Member 3

Ilana Stroke, PhD

Subject(s)

Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Leukemia, Neoplasms, Leukemia, Myeloid, Acute, Leukemia, Lymphocytic, Chronic, B-Cell, Agammaglobulinaemia Tyrosine Kinase

Disciplines

Biological Phenomena, Cell Phenomena, and Immunity | Cancer Biology | Medical Cell Biology | Medical Molecular Biology | Medicine and Health Sciences | Neoplasms

Abstract

Leukemia is the most common childhood cancer, with a combined 40,000 predicted new cases in the United States in 2016 [8]. The two most common subtypes are acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) [9-11]. The commercially available inhibitor of Bruton’s tyrosine kinase (BTK) has shown promising results in clinical trials for CLL because of the importance of BCR signaling in CLL [12-15]. Recent studies suggest that the outgrowth of BTK inhibitor resistant clonal cells in some CLL patients results in a treatment-refractory phenotype [16-18]. MALT1, a protein involved in BCR activation of the NF-κB pathway that functions downstream of BTK, is a promising new target aimed at treating an aggressive BCR signaling-dependent subtype of non-Hodgkin’s lymphoma, known as ABC-DLBCL [1-3, 6]. Targeting this protein for small molecule inhibition may be effective in the treatment of BTKi-refractory CLL patients, as well as other leukemias, such as AML [19]. The effect of MALT1 or BTK inhibition on AML, CLL, and DLBCL cell proliferation was analyzed. Together with examination of protein expression in each cell line and the effect of MALT1 inhibition on cleavage of its downstream target RelB, it is supported that a clinical MALT1 inhibitor would be effective in slowing the growth of CLL, ABC-DLBCL, and AML tumors. Combinatorial experiments supported the hypothesis that combination treatment with MALT and BTK inhibitors could be efficacious at treating patients with relapsed or refractory CLL or ABC-DLBCL.

Recommended Citation

Snyder, Christina, "Characterization of MALT1 Inhibitors and Their Effect on Leukemic Cell Growth Properties" (2017). Graduate School of Biomedical Sciences Theses and Dissertations. 9.
https://rdw.rowan.edu/gsbs_etd/9