Targeting head and neck squamous cell carcinoma through NQO1-mediated cytotoxicity

Francis, Joshua M

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Description

Title

Targeting head and neck squamous cell carcinoma through NQO1-mediated cytotoxicity

Author(s)

Francis, Joshua M

Issue Date

2017-04-24

Director of Research (if dissertation) or Advisor (if thesis)

Hergenrother, Paul J.

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

M.S.

Degree Level

Thesis

Keyword(s)

• Deoxynyboquinone
• Head and neck cancer
• Head and neck squamous cell carcinomas (HNSCC)
• Feline oral squamous cell carcinoma cell lines (FOSCC)
• Radiation
• Chemical biology
• Organic chemistry
• Synthesis

Abstract

Head and neck squamous cell carcinomas (HNSCC) are a group of anatomically diverse cancers characterized by their resistance to traditional chemotherapy and radiotherapy modalities. Given that as diagnostic and therapeutic strategies in cancer treatment have seen great improvements over the last several decades, it would be only logical that the prognosis of HNSCC should improve. However, this has not been the case as the prognosis for HNSCC has remained unchanged over the last several decades, highlighting a need for new treatment strategies. One potential strategy that has demonstrated potential in a variety of other solid tumors is NQO1-targeted therapy. In this strategy the overexpression of NQO1 can be taken advantage of by the DNQ derivative IB-DNQ which is a futile substrate for NQO1 that generates high levels of cytotoxic ROS selectively inside the cancer cell. Given the high prevalence of NQO1 in HNSCC tumors this appears to be a promising strategy for treating this disease. Described in Chapter 2 is the evaluation of IB-DNQ in HNSCC cell lines as well as in feline oral squamous cell carcinoma cell lines (FOSCC). The effectiveness of IB-DNQ was found to be directly correlated with the expression of NQO1 in these cell lines. The pharmacokinetic profile and tolerability of IB-DNQ was determined in healthy research cats and parameters from these analyses were used to conduct in vitro experiments to mimic these conditions. These experiments showed that tumors expressing NQO1 should respond to treatment with IB-DNQ. Preliminary treatments of cats with FOSCC with IB-DNQ as a single agent, as well as in combination with ionizing radiation have yielded positive/promising responses in several cats. Described in Chapter 3 is the investigation into enhancing the current therapeutic window of NQO1-targeted therapy. A prodrug approach to IB-DNQ was attempted to increase solubility and/or reduce off-target toxicity. A secondary approach involving the synthesis of novel derivatives of IB-DNQ containing modifications at a site not previously explored in the SAR of the molecule was also conducted. While the few derivatives synthesized to date all have experienced loss in potency, this site is primed for further investigation and derivatization. Finally, an approach revisiting previously synthesized derivatives of DNQ was implemented in attempts to find a derivative with a greater maximum tolerated dose (MTD) or more favorable pharmacokinetics. Future studies involving NQO1-independent ROS generation, methemoglobin formations and tumor penetrations are currently being investigated to differentiate DNQ derivatives and identify a lead compound. Ongoing clinical evaluation of NQO1-targeted therapy in feline OSCC aims to establish IB-DNQ as an effective treatment modality as well as strengthen its case for translation into humans.

Graduation Semester

2017-05

Type of Resource

text

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Copyright and License Information

Copyright 2017 Joshua M Francis

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