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Exploring Novel PRMT5 Inhibitors for the Treatment of Human and Canine Lymphomas

Sloan, Shelby
http://rave.ohiolink.edu/etdc/view?acc_num=osu168174747151932

Abstract Details

2023, Doctor of Philosophy, Ohio State University, Comparative Biomedical Sciences.
Lymphoma is a cancer that affects white blood cells called “lymphocytes” found in the lymphatic system. Each year approximately 580,000 people are diagnosed with lymphoma. Lymphoma is further categorized as a Hodgkin lymphoma (HL) or a non-Hodgkin lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are two distinct subtypes of NHL that originate from abnormal growth of B-lymphocytes. DLBCL is the most common subtype of NHL whereas MCL is rare, representing ~6% of non-Hodgkin disease. Patients are commonly diagnosed with DLBCL and MCL at a median age of 65 years and present with enlarged or swollen lymph nodes. Other common symptoms are fevers, night sweats, weight loss, loss of appetite, and fatigue. Similarly, lymphoma is one of the most common cancers in dogs with DLBCL being the most common subtype of NHL. MCL is comparatively rare in dogs; however, it tends to be a more indolent disease in dogs and lacks the hallmark translocation of cyclin D1. Treatment for both human and canine lymphoma involves multi-agent cytotoxic combination chemotherapy, with radiation, small molecule targeted therapy, and immuno-therapy. Patients with DLBCL and MCL have a highly variable clinical course; and while most patients respond initially to immuno-chemotherapy many patients do not achieve a durable remission and relapse with drug-resistant disease. There remains an unmet need for more durable and tolerable therapeutic options for the relapsed and refractory patient population. Protein arginine methyltransferase 5 (PRMT5) is a protein that catalyzes the addition of methyl groups to arginine residues on numerous target proteins. PRMT5 is overexpressed in human and canine lymphomas and plays an important oncogenic role by epigenetic and post-translational modification of cell cycle regulators, DNA repair genes, pro-survival signaling components, and RNA splicing. In this dissertation, we explored targeting PRMT5 as a treatment for human and canine lymphomas with small molecule inhibitors of PRMT5 (C220 and PRT-382). Specifically, our studies focused on human MCL and canine DLBCL subtypes. In summary, targeting PRMT5 in vitro led to growth arrest and apoptotic cell death of cell lines and patient samples. Inhibition of PRMT5 resulted in the global loss of PRMT5 prost-translational modifications of symmetrically dimethylated arginine (SDMA) residues. We interrogated whole transcriptomic changes upon PRMT5 inhibition using gene expression microarrays and RNA-sequencing and highlighted key mechanisms of drug action. This work validates targeting PRMT5 in both human and canine lymphomas as a promising therapeutic strategy and supports the continued development of PRMT5 inhibitors in pre-clinical and clinical trials.
Lapo Alinari (Committee Co-Chair)
Robert Baiocchi (Committee Chair)
103 p.
Biomedical Research; Comparative; Oncology

Recommended Citations

Citations

  • Sloan, S. (2023). Exploring Novel PRMT5 Inhibitors for the Treatment of Human and Canine Lymphomas [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu168174747151932

    APA Style (7th edition)

  • Sloan, Shelby. Exploring Novel PRMT5 Inhibitors for the Treatment of Human and Canine Lymphomas. 2023. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu168174747151932.

    MLA Style (8th edition)

  • Sloan, Shelby. "Exploring Novel PRMT5 Inhibitors for the Treatment of Human and Canine Lymphomas." Doctoral dissertation, Ohio State University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=osu168174747151932

    Chicago Manual of Style (17th edition)

osu168174747151932
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This open access ETD is published by The Ohio State University and OhioLINK.