PhD, University of Cincinnati, 2014, Medicine: Cancer and Cell Biology

Innate immune signaling has an essential role in inflammation, and the dysregulation of signaling components within this pathway is increasingly being recognized as a mediator in cancer initiation and progression. The innate immune system is an evolutionarily conserved pathogen pattern recognition apparatus, which defends the host in a non-specific manner. Pathogens and cytokines signal to immune cells through the toll-like receptor (TLR) and interleukin-1 receptor (IL1R) superfamily. In order to mediate an inflammatory response, TLRs and IL1R require interleukin-1 associated receptor kinases (IRAKs). Herein, we demonstrate that IRAK1 is activated and overexpressed in Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); two closely related hematologic malignancies. Furthermore, pharmacological (IRAK-Inh) and RNAi-mediated inhibition of IRAK1 is effective in eliminating disease-propagating cells. Integrated gene expression analysis revealed compensatory BCL2 upregulation following small-molecule IRAK1 inhibition. This proved to be a drugable vulnerability, as BCL2 inhibition potently synergized with IRAK-Inh to induce rapid cell death, even in IRAK-Inh-refractory cell lines. Importantly, suppression of IRAK1 signaling, through either RNAi or small-molecule inhibition, is tolerated in normal CD34+ cells, suggesting a potential therapeutic window for MDS and AML patients. To examine the effect of cancer-modifying therapies, like IRAK inhibition, we developed a novel xenograft model, utilizing an MDS-derived patient cell line, MDSL. Immunocompromised animals receiving MDSL xenografts developed progressive anemia and thrombocytopenia, thus recapitulating clinical features of the disease. These mice displayed rapid morbidity resulting from MDSL engraftment in bone marrow, spleen and peripheral blood. In this setting, both RNAi-mediated and small-molecule IRAK1 inhibition was effective in reducing MDSL cell burden, and provided a significant survival benefit. T (open full item for complete abstract)

Committee: Daniel Starczynowski Ph.D. (Committee Chair); Gang Huang Ph.D. (Committee Member); H. Leighton Grimes Ph.D. (Committee Member); Ashish R. Kumar M.D. Ph.D. (Committee Member); Maria Czyzyk-Krzeska M.D. Ph.D. (Committee Member); James Mulloy Ph.D. (Committee Member) Subjects: Cellular Biology

Doctor of Philosophy, The Ohio State University, 2009, Veterinary Biosciences

Prostate cancer is the most commonly diagnosed noncutaneous cancer and the second leading cause of cancer death in men. To combat the assortment of genomic and cellular aberrations that occur with the progression of this disease, we have developed novel classes of histone deacetylase (HDAC) inhibitors, 3-phosphoinositide dependent protein kinase-1 (PDK1)/Akt inhibitors, and indole-3-carbinol analogs using phenylbutyrate, celecoxib, and indole-3-carbinol, respectively, as scaffolds. Here, we assess both the efficacy and safety of the lead compounds of these classes (OSU-HDAC42, OSU-03012, and OSU-A9) administered orally in a series of preclinical studies carried out, in part, in preparation for prevention and regression trials in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Following the acquisition of relevant in vitro and dose-ranging data, the tumor-suppressive efficacy of selected doses was evaluated in PC-3 xenograft ± TRAMP-C2 syngeneic mouse models. The oral drug formulation found to achieve the most promising benefit-risk ratio was incorporated into a diet and administered to TRAMP mice for the assessment of its morphologic and molecular effects on the development of prostatic intraepithelial neoplasia (PIN) and carcinoma. Toxicity was evaluated by histopathologic, hematologic, and body and organ weight analysis. OSU-HDAC42 achieved the most potent blockade of prostate tumorigenesis reported in the TRAMP model, suppressing the absolute and relative weights of the urogenital tracts by 86% and 85%, respectively, in association with intraprostatic modulation of biomarkers indicative of HDAC inhibition, increased apoptosis and differentiation, and decreased proliferation. This compound, while sparing body weight, caused reversible testicular degeneration and hematologic alterations. In addition to its prostate chemopreventive effects, OSU-03012 was found to induce the hepatic biotransformation enzymatic system and caused phenotypic changes p (open full item for complete abstract)

Committee: Ching-Shih Chen PhD (Advisor); Robert Brueggemeier PhD (Committee Member); Steven Clinton MD, PhD (Committee Member); Thomas Rosol DVM, PhD (Committee Member) Subjects: Animals; Biochemistry; Health Care; Molecules; Oncology; Pathology; Pharmaceuticals; Pharmacology; Therapy; Toxicology; Veterinary Services