Doctoral Dissertations

Date of Award

12-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Life Sciences

Major Professor

Maria Cekanova

Committee Members

Maitreyi Das, Robert Donnell, Katie Tolbert, Albrecht von Arnim

Abstract

Several types of cancer, including bladder cancer, overexpress multiple receptor tyrosine kinases (RTKs), such as the c-Kit receptor and platelet derived growth factor receptor (PDGFR). Inhibitors of RTKs (RTKIs) are therefore used as targeted treatment options for patients with cancers that overexpress RTKs. A challenge associated with targeted therapies is the activation of alternative pro-survival signaling pathways, such as the cyclooxygenase-2 (COX-2) pathway, resulting in drug resistance. Although COX-2 is over-expressed and promotes tumorigenesis in bladder cancer, it can be used as a biomarker for bladder cancer detection and treatment strategies.Conventional optical imaging technologies can detect advanced stages of bladder cancer; however, they have several limitations to detect early stages. Novel optical imaging agent, fluorocoxib A, is a rhodamine-conjugated analog of indomethacin, which selectively targets COX-2 expressing tissues. Fluorocoxib A can be used for the detection and monitoring of COX-2-expressing tumors during treatment.We evaluated the effects of RTKIs and COX inhibitors, alone and in combination, on human and canine bladder cancer cell lines in vitro. Despite inhibiting cellular proliferation and increasing apoptosis, tested RTKIs increased COX-2 expression. Co-treatment of RTKIs and COX inhibitors abrogated the RTKI-induced COX-2 expression, indicating co-treatment may be more effective than either treatment alone.To evaluate the ability of fluorocoxib A for the detection of bladder cancer in mice, we used the carcinogen (N-butyl-N-4-hydroxybutyl nitrosamine, BBN) -induced bladder cancer mouse model that resembles human bladder cancer. The specific uptake of fluorocoxib A by the bladder tissues correlated with the progression of bladder carcinogenesis and increased COX-2 expression, in contrast to normal bladder urothelium where no fluorocoxib A uptake was detected.We also investigated the RTKI-induced upregulation of COX-2 by evaluating the effects of RTKIs in vivo. Treatment of K9TCC#5Lilly xenograft tumors with AB1010 and imatinib increased COX-2 levels in the tumors of treated mice compared to the control group. The specific uptake of fluorocoxib A correlated with the treatment-induced increased COX-2 expression.Our results suggest that fluorocoxib A is a valuable optical imaging agent that can be used for detecting and monitoring early responses to targeted therapies in patients diagnosed with COX-2-expressing bladder cancer.

Comments

Research article described in Chapter II is a slightly modified version of an article that was published in the Dove Press journal, Drug Design, Development, and Therapy, by Jennifer Bourn and Maria Cekanova in June 2018.

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