Master of Science, The Ohio State University, 2024, Anatomy

Introduction Lung cancer is prevalent and deadly and contributes to approximately 25% of all cancer-related mortalities. With incidence rates rising globally, new treatment options have increased patient overall survival. Lung cancer is unique from other cancer types in that there is a correlation between a patient's body mass index (BMI) and overall survival. Sarcopenia is a skeletomuscular system disorder characterized by a loss of skeletal muscle mass, size, and function. It is identified to be correlated with worse treatment outcomes and survival in several cancer types. Thus, this study explored the relationship between anatomically measured sarcopenia and survival. We hypothesized that sarcopenia would be correlated with a worse overall survival among patients with non-small cell lung cancer. Additionally, we tested two anatomically different measurement methods. Methods We abstracted data from both chest and abdominal CT scans from 22 patients consented and enrolled in the FITNESS Study: Longitudinal Geriatric Assessment, Treatment Toxicity, and Biospecimen Collection to Assess Functional Disability Among Older Adults with Lung Cancer at the Ohio State Wexner Medical Center's James Cancer Hospital and Solove Research Institute. Using the NilRead software, the skeletal muscle index (SMI) was analyzed by finding the paravertebral muscles at the T12 level, and the psoas major muscle at the L3 level, and manually tracing it to calculate the SMI. Additionally, the patient's weight, in kg, and height, in meters, were used to calculate their BMI as the same date of their baseline CT scans. The patient's body mass index (BMI) and SMI values for both methods were analyzed and further assessed by patient sex. From there, previously established equations were utilized to calculate the sarcopenic and normal range SMI values for both methods. Next, univariate and multivariate Hazard Cox Ratio tests were run to analyze the impact on survival. A paired samples T-Test wa (open full item for complete abstract)

Committee: Melissa Quinn (Advisor); Jessica Blackburn (Committee Member); Carolyn Presley (Committee Member) Subjects: Anatomy and Physiology; Medical Imaging; Medicine

Doctor of Philosophy, Case Western Reserve University, 2024, Pharmacology

Breast cancer is a heterogeneous disease with each subtype varying in treatment options, regimens, and limitations. The Luminal A, Luminal B, and HER2 subtypes are treated with targeted therapies that extend patient life. However, resistance to these primary therapies may arise and additional targeted therapies are applied to overcome resistance. The triple negative breast cancer (TNBC) subtype is highly aggressive and has limited targeted therapies, making the identification of targetable drivers a priority. The work presented herein, takes two approaches to identify novel treatments for breast cancer patients by 1) uncovering targetable resistance mechanisms to enhance the efficacy of select targeted therapies and 2) identifying targetable drivers of the disease that can be leveraged as a therapeutic option. Targeted therapy everolimus (mTORC1 inhibitor) is utilized in Luminal A breast cancer patients resistant to previous anti-hormone therapies. In the first project, we set out to identify mechanisms that render limited efficacy of mTORC1 inhibition. Short term treatment with rapamycin, a prototypical mTORC1 inhibitor, caused differential expression of genes regulating the extracellular matrix (ECM) organization. Focal adhesion kinase (FAK) is recruited to integrins that can recognize changes in the ECM. Inhibiting FAK increased rapamycin efficacy in mTORC1-inhibitor resistant tumors. In the second project, we identified the Src Family Kinase, YES1, is highly expressed in TNBC and is a driver of growth. YES1 maintains EGFR expression through the regulation of JNK signaling and c-Jun transcription. We additionally found that YES1 regulates wildtype and mutant forms of EGFR in non-small cell cancer (NSCLC) models. YES1 selective inhibitors synergize with EGFR inhibitors in TNBC and NSCLC in vitro and in vivo. Taken together, we uncovered targeted vulnerabilities to enhance the efficacy of FDA-approved inhibitors and thus have identified novel combination (open full item for complete abstract)

Committee: Ruth Keri (Advisor); Marvin Nieman (Committee Chair); Bingcheng Wang (Committee Member); Corey Speers (Committee Member); George Dubyak (Committee Member) Subjects: Biology; Pharmacology

Master of Science (MS), Wright State University, 2023, Biochemistry and Molecular Biology

Extracellular signal related kinase 3 (ERK3) is one of the atypical mitogen activated protein kinases (MAPK). It is expressed ubiquitously and plays a role in a variety of cellular processes, including cell growth and differentiation. ERK3's role in promoting migration and invasion in various cancers has been well established. ERK3 is upregulated in non-small cell lung cancers (NSCLCs) and has been shown to promote NSCLC tumor growth and progression. However, the regulation of ERK3 in lung cancers remains largely unclear. A recent study indicates that ERK3 phosphorylation at S189, an indicator of ERK3 activity, is upregulated by KRAS in NSCLCs. KRAS is one of the most commonly mutated oncogenes in lung cancers. To study the KRAS dependent regulation of ERK3, knockdown of KRAS was performed and it resulted in a remarkable reduction in ERK3 phosphorylation as well as total ERK3 protein level confirming the regulation of ERK3 by KRAS. Upon knockdown of KRAS a significant reduction of ERK3 mRNA level was observed indicating that KRAS regulates ERK3 at transcriptional level. Further, we found that the regulation of ERK3 by KRAS may be through the transcription factor c-Jun, that is well-known to be activated by KRAS signalling. Our data indicates that c-Jun positively regulates ERK3 transcription in LUAD cell lines. Further, we have found that KRAS upregulates c-Jun activating phosphorylations in LUAD cells, suggesting that KRAS regulates ERK3 through c-Jun. Given the discrepancy regarding the role of ERK3 in NSCLC cell growth reported in previous studies, we have thoroughly investigated the role of ERK3 in cell growth by stable knockdown of ERK3 using shRNA targeting different regions of ERK3 mRNA, as well as by using ERK3 inhibitors in a variety of NSCLS cell lines. While knockdown of ERK3 via targeting the coding region did not affect cell proliferation, targeting the 3'UTR of ERK3 or treatment with ERK3 inhibitors reduced the proliferation of LUAD cells.

Committee: Weiwen Long Ph.D. (Advisor); Kwang-Jin Cho Ph.D. (Committee Member); Michael Craig Ph.D. (Committee Member) Subjects: Biochemistry; Molecular Biology

Doctor of Philosophy, The Ohio State University, 2019, Biomedical Sciences

LKB1 is the fourth-most frequently mutated gene in lung adenocarcinoma, with loss-of-function observed in up to 30% of all cases (Collisson et al. 2014; Kaufman et al. 2014). Our previous work identified a 16-gene signature for LKB1 loss of function through not just mutation, but deletion and epigenetic silencing, which occurs relatively frequently (Lee et al. 2013; Kaufman et al. 2014). We applied this genetic signature to lung adenocarcinoma samples in the Cancer Genome Atlas (TCGA) and discovered a novel association between LKB1 loss and widespread CpG demethylation. LKB1-loss tumors also expressed significantly less DNA methyl transferase (DNMT1) and show depletion of S-Adenosyl-Methionine (SAM-e), which is the primary substrate for DNMT1 activity. Repetitive element transcriptional start sites are demethylated and sensitivity to azacytidine is lower in LKB1 loss. Mechanistically, demethylated CpGs are enriched for FOXA1/2/3 consensus binding sites, and we further identified that FOXA localization and turnover is dependent upon LKB1 and the downstream kinase SIK. Overall, these findings demonstrate that a large number of lung adenocarcinoma patients have a unique epigenetic profile driven by LKB1 loss which could play a role in lung tumorigenicity and resistance to immunotherapy.

Committee: David Carbone (Advisor); Christopher Oakes (Committee Member); Matthew Ringel (Committee Member); Susan Cole (Committee Member); Sameek Roychowdhury (Committee Member) Subjects: Bioinformatics; Biology; Biomedical Research; Genetics; Oncology

Doctor of Philosophy, University of Akron, 2015, Chemistry

N,N'-substituted imidazolium salts are incredibly versatile compounds that have found applications across a variety of fields. They can be chemically modified through straightforward procedures, allowing for the synthesis of imidazolium salts with vastly differing properties. This dissertation explores the potential biological applications of mono- and bisimidazolium salts as new chemotherapeutic agents for the treatment of non-small cell lung carcinomas (NSCLC) and as chemical exfoliating agents for the treatment of recurrent urinary tract infections. Chapter I of this dissertation reviews the basic nomenclature and structure of imidazolium salts. Past and current research toward the biological applications of imidazolium salts and their use as precursors to N-heterocyclic carbene complexes is summarized. Chapter II explores the activity of a series of monoimidazolium salts against a panel of NSCLC cell lines. The treatment of lung cancer remains frustratingly difficult, and lung cancer maintains one of the highest mortality rates among cancer types. Current treatment options are only marginally effective and are plagued by severe side effect profiles or eventual resistance of the cancers to treatment. Therefore, there is a pressing need to develop new chemotherapeutic agents for the treatment of lung cancer. In this chapter, the in vitro antiproliferative activity of monoimidazolium salts against several NSCLC lines are determined by the MTT cell viability assay. The degree of apoptotic cell death is investigated by the use of the Annexin V-FITC/PI apoptosis detection assay, and possible imidazolium salt interactions with DNA are probed by a fluorescent intercalator displacement assay. Chapter III focuses on the synthesis of a series of bisimidazolium salts designed to mimic the activity of the bisintercalating agent echinomycin. The in vitro antiproliferative activity of these bisimidazolium salts and their potential interactions with DNA were determined (open full item for complete abstract)

Committee: Wiley Youngs Dr. (Advisor); Claire Tessier Dr. (Committee Member); Peter Rinaldi Dr. (Committee Member); Sailaja Paruchuri Dr. (Committee Member); Edward Evans Dr. (Committee Member) Subjects: Biochemistry; Chemistry