Bachelor of Science (BS), Ohio University, 2022, Biological Sciences

Lung cancer is the second most prevalent cancer in both men and women in the United States, and it currently the leading cause of cancer-related deaths. While there are current standard treatments for lung cancer, these treatments are not effective enough, and can lead to drug resistance, severe side effects, and even recurrence of the cancer and death. It is easy to see that better anticancer therapies are urgently needed. It has been shown that many cancer types, including Non-Small Cell Lung Cancer (NSCLC), which makes up 84% of all lung cancer diagnosis, are addicted to glucose and are sensitive to glucose deprivation, ultimately resulting in cancer cell-death. DRB18 is a small molecule compound developed at Ohio University that has been shown to target and inhibit glucose transporters (GLUTs), which are responsible for the uptake of glucose into cells, particularly cancer cells. DRB18 has been shown to be effective in inhibiting cancer cell growth in vitro (cell culture) and in vivo (nude mice) without noticeable side effects. While this may be a promising anticancer therapy by itself, combining DRB18 with an FDA-approved anticancer drugs Paclitaxel, Trametinib, or Brigatinib maximized the efficacy of the treatment in vitro in NSCLC A549 cells, and combination treatment of DRB18 + Paclitaxel resulted in shrunken A549 xenograft tumors in vivo, without increasing unwanted side effects. This combination therapy has the potential to benefit cancer patients for decades to come.

Committee: Soichi Tanda (Advisor); Xiaozhuo Chen (Advisor) Subjects: Biology; Biomedical Research; Medicine; Oncology

Doctor of Philosophy, The Ohio State University, 2022, Biomedical Sciences

Small cell lung cancer (SCLC) is an extremely aggressive neuroendocrine tumor, accounting for approximated 13% of all lung cancer cases. SCLC is characterized by rapid growth and early metastasis. Despite marked improvements in the number and efficacy of targeted, therapeutic options and overall survival rates in SCLC have remained nearly unchanged for almost three decades. The lack of significant progress can be attributed to our poor understanding of the biology of SCLC. Although immune checkpoint inhibitors were recently approved as front-line therapies for SCLC, we still need to better understand the mechanisms responsible for the selective vulnerability of some SCLCs to these inhibitors. Recent work utilizing sequencing data and single cell analyses identified four distinct subsets of SCLC, based on the expression levels of the transcription factors ASCL1, NEUROD1, POU2F3 and YAP1. Each subset was found to have its own distinct biology and therapeutic vulnerabilities. However, these subsets appear to be phenotypically unstable, representing snapshots in the gradual evolution of a tumor that exhibits significant plasticity. Tumor evolution, a product of this plasticity, results in the emergence of significant intratumoral heterogeneity which plays an important role in multiple aspects of SCLC development and progression, including cell survival and proliferation, metastasis and angiogenesis. The recent paradigm shifting discoveries in the biology of SCLC are now beginning to inform the design of new therapeutic strategies for the management of this intractable disease. Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) is an oncofetal protein that is emerging as a therapeutic target and is co-expressed with BCL2 in multiple tumor types due to microRNA coregulation. We hypothesize that ROR1-targeted therapy is effective in small cell lung cancer and synergizes with therapeutic BCL2 inhibition. Tissue microarrays (TMAs) and formalin-fixed paraffin-embedded (F (open full item for complete abstract)

Committee: David Carbone (Advisor); Matthew Ringel (Committee Member); Carlo Croce (Committee Member); Philip Tsichlis (Committee Member) Subjects: Biology; Biomedical Research; Oncology

Master of Science, The Ohio State University, 2016, Biomedical Sciences

Sorafenib therapy has been shown to have only a small clinical benefit for liver cancer patients. There is an urgent needed to develop new therapeutic strategies for the treatment of advanced stage HCC. In this report, we screened several repurposed therapeutics in order to identify synergistic drug combinations. We demonstrate that the combination of 2-deoxy-glucose and sorafenib drastically inhibit HCC cell viability in Hep3B, Huh7 and sorafenib resistant Huh7 cells. Cell cycle analysis revealed that this therapeutic combination induced complete G0/G1 arrested HCC cells. Our studies suggest that this cell-cycle arrest is due to the depletion of cellular ATP. Overall, this report provides strong evidence for the clinical potential of sorafenib + 2-deoxyglucose combination therapy.

Committee: Samson Jacob PhD (Advisor); Kalpana Ghoshal PhD (Committee Member) Subjects: Medicine; Molecular Biology; Therapy

MS, University of Cincinnati, 2016, Medicine: Genetic Counseling

Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase leading to accumulation of globotriaosylceramide (GL3) primarily in the vascular endothelium. This accumulation causes a variety of daily and long-term problems including gastrointestinal issues, depression, and chronic nerve, muscle, and joint pain. Long-term complications include heart disease, kidney failure, and stroke. The only FDA approved treatment for Fabry disease (other than symptomatic management) is biweekly enzyme replacement therapy (ERT). ERT is costly (greater than $200,000 per year on average), burdensome (IV infusions lasting 4-6 hours often at clinics far from home), has been associated with unpleasant infusion reactions, and has only been found to slow or delay onset of long-term complications. Consistent improvements in daily signs and symptoms of Fabry disease have not been observed. Several pharmaceutical companies are working to develop additional primary and/or adjunctive therapies to improve the safety, efficacy, and burden of treatment. Little research has been done on which factors influence the willingness of a patient with Fabry to follow a prescribed treatment plan. We developed a questionnaire based upon hypothetical scenarios to try to vet which factors most influence someone's decision to begin treatment for Fabry disease and how much they are willing to do based upon various improvements. The questionnaire was distributed to adults with Fabry disease and parents/guardians of children with Fabry disease. Participants were recruited while attending the NFDF 2015 Annual Fabry Conference in North Carolina and from Cincinnati Children's Hospital Medical Center. We present results based upon 45 completed questionnaires highlighting the factors that most influence an individual's decision to start or continue a treatment plan for his/herself or their child. Factors that appear to have the most influence include improvement in long-term co (open full item for complete abstract)

Committee: Robert Hopkin M.D. (Committee Chair); Laurie Bailey M.S. (Committee Member); Lisa Berry M.S.C.G.C. (Committee Member); Valentina Pilipenko Ph.D. (Committee Member) Subjects: Genetics

PhD, University of Cincinnati, 2023, Medicine: Cancer and Cell Biology

Rhabdomyosarcoma (RMS) is an aggressive, metastatic cancer that arises predominantly in children. RMS is highly recurrent, developing resistance to current treatments, indicating the need for new therapies. FOXM1 is a well-known oncogene that is overexpressed in RMS, and is associated with a worse prognosis. Targeting of FOXM1 leads to a reduction of tumor proliferation and induction of tumor cell death. However, there are no clinically approved therapies that target FOXM1. We recently identified a small molecule inhibitor of FOXM1, RCM1, that has shown high efficacy across multiple tumor types, including RMS, and is non-toxic in vivo. Interestingly, RCM1 also increases the duration of mitosis in tumor cells, indicating that the combination with RCM1 and another cell-cycle specific therapeutic could have combinatorial effects and increase efficacy on tumor burden. Vincristine (VCR) is a first line of defense for RMS patients but is toxic, so VCR is typically used in combination to combat these toxic effects. In the studies within this dissertation, we aimed to characterize the effects of RCM1 and VCR in RMS, which took much optimization. RCM1 has extremely low solubility, and previous efforts to dissolve RCM1 in solution have only been successful using pure DMSO or a DMSO cocktail, which lead to insufficient administration and efficacy in vivo and in vitro across human and murine derived RMS. Despite this, we did observe a strong reduction of RMS cell counts after combination treatment in both murine and human derived RMS in vitro using IC50 doses of RCM1 and VCR. These results also demonstrated that the combination therapy reduces proliferation and induces apoptosis more effectively compared to single agents and control. Interestingly, subcutaneous models showed improved efficacy to both RCM1 and VCR compared to orthotopic models. We also developed a nanoparticle delivery system capable of encapsulating RCM1 in vivo through optimization of multiple types of nanopar (open full item for complete abstract)

Committee: Tanya Kalin M.D. Ph.D. (Committee Chair); Nicolas Nassar Ph.D. (Committee Member); Sara Szabo Ph.D. M.D. (Committee Member); Carolyn Price Ph.D. (Committee Member); David Plas Ph.D. (Committee Member) Subjects: Oncology

Doctor of Philosophy, Case Western Reserve University, 2023, Molecular Medicine

The effector function of cytotoxic lymphocytes (CTLs) is precisely managed through TCR MHC engagement, co-stimulatory axis as well as co-inhibitory pathways. Due to the deprived environment in a tumor and persistent antigen stimulation, CTLs lose their ability to effectively kill malignant cells, rendering them dysfunctional and exhausted. One reason is because they upregulate co-inhibitory surface proteins that reduce the activation of the T cell and therefore its effector function. Immune checkpoint inhibitors (ICI) are a class of immunotherapies targeting immune checkpoint proteins with the intention of restoring anti-tumor immunity. Anti-CTLA4 was the first ICI to gain FDA approval, and anti-PD1 is the second, both have been investigated heavily to optimize the benefit to the patient. Due to the non-redundant, yet sometimes convergent, nature of the ICs pathway it has been shown that combination therapies are providing additional benefit to the patients. Therefore, it is imperative that we continue to fund and study emerging checkpoint proteins stand alone and in combination treatment with other ICIs or other immunotherapies. This thesis examines VISTA, an emerging immune checkpoint protein, on CD8+ T cells in the tumor. We make the case that genetic deletion of VISTA allows for superior T cell function and less exhaustion with a more diverse T cell receptor (TCR) repertoire and more tumor control with combination therapy. VISTA, without any signaling domains, is largely thought of as a ligand. We sought to understand how deleting a ligand can have such potent T cell intrinsic effects, so we explored potential CIS binding receptors in the tumor. We discovered that VISTA binds another immune checkpoint receptor (ICR) and has measurable TCR and AKT signaling pathway suppression via the ICR's signaling cytoplasmic tail. This thesis helps to bridge the knowledge gap of whether VISTA has receptor properties and T cell intrinsic effects in the tumor.

Committee: Li Lily Wang (Advisor); George Thomas Budd (Committee Member); Booki Min (Committee Member); Justin Lathia (Committee Chair) Subjects: Biology; Immunology; Molecular Biology; Oncology

PHD, Kent State University, 2019, College of Arts and Sciences / School of Biomedical Sciences

Neuroinflammation, a hallmark of many neurodegenerative diseases is mediated by microglia, the primary immune cells of the central nervous system (CNS). Activated microglial cells respond to neuronal injury and remove cellular debris, infectious agents via phagocytosis conferring neuroprotection. However, the chronic activation of these cells impairs neuronal function through the excessive release of NO and proinflammatory cytokines TNF-α and interleukins (IL-6, IL-1β and IL-12) which contributes to neuroinflammation and subsequent neurodegeneration in the brain. Thus, suppressing microglial activation is an effective therapeutic strategy to combat neuroinflammation associated with degenerative brain diseases. While anti-inflammatory agents are required to treat neurodegeneration, they may not be sufficient on their own as the disorder is multifaceted and complex but may be effective as part of a combination therapy. Therefore, improved treatment options focused on combinatory neuroprotective effects of simvastatin (Sim) and brain derived neurotrophic factor (BDNF), seem most beneficial in restoring CNS damage, as Sim is known to inhibit inflammation, promote cell survival and BDNF is a predominant neurotrophic factor that mediates survival and growth of a variety of neurons in the CNS. However, the delivery of combination therapeutics that hold promise for the treatment of neurological disorders lack clinical efficacy due to their inability in reaching high enough concentrations in the brain primarily due to the blood brain barrier (BBB), blood-cerebrospinal fluid (CSF) barrier, presence of efflux systems, enzymatic degradation, and several other factors such as rapid clearance from circulation and off-target effects. This calls for the need to develop an efficient drug delivery system (DDS) to overcome obstacles that impede CNS drug delivery and alternate approaches to bypass the BBB. Since microglia function as macrophages, the DDS must be also be effectively rem (open full item for complete abstract)

Committee: Moses Oyewumi Ph.D. (Committee Chair); Werner Geldenhuys Ph.D. (Committee Member); Fayez Safadi Ph.D. (Committee Member); Denise Inman Ph.D. (Committee Member); Douglas Delahanty Ph.D. (Committee Member) Subjects: Biomedical Research; Nanoscience; Nanotechnology; Pharmacology

PhD, University of Cincinnati, 2017, Engineering and Applied Science: Chemical Engineering

Cancer is still a major threat to public health worldwide. Thanks to the extensive studies in cancer biology and growing understanding in cancer, many novel and effective therapeutic agents and drug combinations have been discovered and designed. However, many of them are challenged in reaching their targeted site. Nano-scaled drug carriers that target and deliver therapeutic agents to the sites of diseases have shown great promises in cancer treatment. As a starting point, we designed a human epidermal growth factor receptor 2 (HER-2) targeting pH sensitive nanoparticle combining the advantages of polyhistidine (PHis) and Herceptin. This nanoparticle contains a pH sensitive hydrophobic core in which chemotherapeutic drug is loaded and hydrophilic layer which stabilizes the whole nanoparticle while providing active targeting to HER-2. This nanoparticle shows a pH triggered drug release (i.e. fast drug release at acidic condition and sustained release at physiological condition), a capability of endosomal escape which allows delivery of cargo to cytoplasm, and HER-2 targeting which enhances cellular uptake of the nanoparticle. This work is described in detail in chapter 2. In addition, there are growing needs in delivery of micro RNA inhibitor (miRi) for RNA interferences (RNAi). In chapter 3, a novel lipid coated calcium phosphate miRi complex was made to address poor encapsulation of hydrophilic RNA molecules in hydrophobic polymeric core for co-delivery of molecules with different physicochemical properties. This novel complex was co-encapsulated with paclitaxel in nanoparticle to achieve co-delivery. The co-delivery nanoparticle was found effective in regulating gene expression in vitro. The synergistic effects of co-delivery of miRi and paclitaxel were confirmed in culture cells. In the last part of the study, chapter 4-5 were focused on developing drug delivery systems address the unmet needs for systematic sequential delivery of combination th (open full item for complete abstract)

Committee: Joo Youp Lee Ph.D. (Committee Chair); Chia Chi Ho Ph.D. (Committee Member); Yoonjee Park Ph.D. (Committee Member); Susan Waltz Ph.D. (Committee Member) Subjects: Chemical Engineering

Doctor of Philosophy, The Ohio State University, 2009, Pharmacy

Chemotherapeutical agents with various mechanisms are generally used in combinations to achieve better efficacy, overcome resistance, and reduce side effects. Although combination chemotherapy showed success in some cases, the selection of anticancer agents for combination therapy and their dosing scheme remain to be further evaluated and optimized. In this dissertation, mechanism-based computational models were developed to study pharmacological actions of single anticancer drugs as well as their combinations. The models were based on the cell cycle kinetics of cancer cells and predicted multiple endpoints that are important to treatment outcome, such as apoptosis, senescence, clonogenicity and polyploid. These models have the potential to be applied in the optimization of chemotherapy regimen, either for monotherapy or combination therapy. In Chapter 2, the antagonistic effect of high dose suramin on paclitaxel was evaluated. A pharmacodynamic model was established to describe suramin-induced cell cycle arrest. This model was integrated with the pharmacodynamic model of paclitaxel to simulate effects after combination treatments. The integrated model predicted antagonism, indicating that the partial cell-cycle block induced by suramin can explain the observed antagonism on paclitaxel effect at elevated suramin concentrations. Chapter 3 established a pharmacodynamic model of the DNA-damaging agent cisplatin. The model successfully predicted in vitro cisplatin effects. A pharmacodynamic model of suramin was developed in Chapter 4 and integrated with the pharmacodynamic model of cisplatin. The model described suramin alone effects as well as effects after combination treatments of suramin and cisplatin. The model was able to predict the biphasic effects of suramin in cisplatin-treated cancer cells. Chapter 5 linked the pharmacodynamic model of cisplatin with a pharmacokinetic model of cisplatin in mice, which was developed based on literature reported data. The in (open full item for complete abstract)

Committee: Jessie Au (Advisor); Guillaume Wientjes (Advisor); Dennis McKay (Committee Member); Matthew Allen (Committee Member) Subjects: Oncology; Pharmaceuticals

Doctor of Philosophy, The Ohio State University, 2009, Pharmacy

In the United States, breast cancer is the most common non-skin malignancy and the second leading cause of cancer-related death in women. However, earlier detection and new, more effective treatments may be responsible for the decrease in overall death rates. Approximately 60% of breast tumors are estrogen receptor (ER) positive and thus their cellular growth is hormone-dependent. Elevated levels of estrogens, even in post-menopausal women, have been implicated in the development and progression of hormone-dependent breast cancer. Hormone therapies seek to inhibit local estrogen action and biosynthesis, which can be produced by pathways utilizing the enzymes aromatase or steroid sulfatase (STS). Cyclooxygenase-2 (COX-2), typically involved in inflammation processes, is a major regulator of aromatase expression in breast cancer cells.STS, COX-2, and aromatase are critical for estrogen biosynthesis and have been shown to be over-expressed in breast cancer. While there continues to be extensive study and successful design of potent aromatase inhibitors, much remains unclear about the regulation of STS and the clinical applications for its selective inhibition. Further studies exploring the relationships of STS with COX-2 and aromatase enzymes will aid in the understanding of its role in cancer cell growth and in the development of future hormone-dependent breast cancer therapies. After confirming the high potency of two STS enzyme inhibitors DU-14 and DU-15 in MCF-7 and MDA-MB-231 breast cancer cells, our initial studies investigated the effects of these compounds on STS, aromatase and COX-2 gene expression by Real-Time RT-PCR, on cancerous cellular growth using the Promega(R) MTS assay, and on STS enzyme activity using a tritium conversion radioassay. We then examined the individual effects, if any, of several COX isozyme inhibitors (celecoxib, NS-398, SC-560 and six non-steroidal anti-inflammatory drugs), aromatase inhibitors (letrozole and exemestane), and anti-est (open full item for complete abstract)

Committee: Pui-Kai Li PhD (Advisor); Robert Brueggemeier PhD (Advisor); Karl Werbovetz PhD (Committee Member); Charles Shapiro MD (Committee Member) Subjects: Biochemistry; Molecular Biology; Oncology; Pharmaceuticals

Doctor of Philosophy, The Ohio State University, 2007, Pharmacy

Pancreatic cancer is the fourth leading cause of cancer death. Due to the complexity of pancreatic cancer in various biochemical and genetic abnormalities especially under hypoxia, the therapeutic regimen is rather limited. Thus inhibition of heat shock protein 90 (HSP90) to simultaneously down-regulate multiple oncogenic proteins would have potential anti-pancreatic cancer effect especially under hypoxia. In addition, high glycolysis rate presents in various solid tumors due to hypoxia, which has been confirmed by positron emission tomography (PET) in human pancreatic tumor. Therefore, we hypothesize to simultaneously target the hypoxic pancreatic cancers by HSP90 inhibitor to down regulate multiple oncogenic proteins and to inhibit the energy production by glycolysis inhibitor for synergistic effect of pancreatic cancer therapy. Primary human pancreatic tumors showed constantly high expression of HSP90 and other oncogenes. The immunostaninging of tissue micro-array for 72 human pancreatic cancer patients indicated the high level of cytoplasmic staining for HSP90, p-AKT, VEGF, and HKII. HSP90 inhibitor, geldanamycin (GA), exhibited more than 10-fold stronger anti-tumor effect via induction of more client protein degradation such as HIF1a and AKT under hypoxia. Furthermore, glycolysis inhibitorsm, 3-Bromo-pyruvate (3-BrPA), showed selective inhibition of high glycolysis in pancreatic cancers under hypoxia and with the preferential inhibition of high rate of glycolysis under hypoxia, 3BrPA sensitized the anticancer effect of GA by 17 to 400-fold in pancreatic cancer cells. The synergistic anti-tumor effect of geldanamycin and 3-BrPA was confirmed in a xenograft model and RIP1-Tag2 transgenic pancreatic tumor model in vivo as measured by tumor growth, AKT degradation as the surrogate marker, and evaluated by non invasive MRI tumor imaging. Combination treatments with GA and 3BrPA showed more than 75% and 90% inhibition on the tumor growth in human pancreatinc cancer x (open full item for complete abstract)

Committee: Duxin Sun (Advisor) Subjects: Health Sciences, Pharmacy

MS, Kent State University, 2010, College of Arts and Sciences / Department of Chemistry

Resveratrol, a naturally occurring polyphenol found in grapevines and other plants, has been shown to have anti-cancer, anti-viral, and other activities. The specific aim of this thesis research was to evaluate and compare the antitumor activities of resveratrol alone and in combination with ascorbate against a panel of two human tumor cell lines (DU145 and MDAH) using a micro-tetrazolium (MTT) assay. Triplicate samples were assayed 12, 24, 48, and 72 hours after continuous treatments, with twelve concentrations of resveratrol and three or five combination ratios tested per time point. The FIC index, which is a marker of synergism, was calculated. Results indicated that resveratrol and ascorbate acted synergistically, reducing the time and concentrations of each component necessary to achieve an effective cytotoxicity level in hormone-independent cancer cell lines. The systematic studies and analyses of resveratrol-ascorbate combinations presented in this study have clinical significance for the evaluation and development of combination chemotherapy for the treatment of various cancer diseases.

Committee: Chun-che Tsai (Committee Chair); Bransidhar Datta (Committee Member); Nicola Brasch (Committee Member); James Jamison M (Committee Member) Subjects: Biochemistry; Pharmaceuticals; Pharmacology