Little progress has been made in the treatment of head-and-neck squamous cell carcinoma (HNSCC) in decades, and there are no impactful targeted therapies for this deadly cancer. The overexpression of the enzyme NQO1 has been observed in a high percentage of primary HNSCC tumors, including in those HNSCC patients with the worst prognoses, and thus compounds that are toxified by NQO1 have the potential to induce marked tumor regression for a desperate patient population. We have obtained a substantial amount of data showing the natural product deoxynyboquinone (DNQ) and its derivatives are potently cytotoxic in cells that express NQO1. As NQO1 is elevated in HNSCC but has low expression in normal tissue, DNQ and its derivatives have the potential as targeted drugs for HNSCC. In addition to significant in vitro and cell culture data on DNQ and derivatives, we have also made pharmacokinetic, toxicity, and efficacy assessments in mouse models of cancer and ? excitingly ? in pet cats with spontaneous HNSCC. Feline HNSCC is very similar to the human disease and is regarded as a significantly more representative and challenging pre-clinical model, thus our data showing activity of a DNQ derivative in these pet cats with spontaneous HNSCC in a NQO1-dependent fashion is very promising. DNQ and its derivatives we have identified thus far do not have the proper therapeutic index to become drugs, that is, their NQO1-independent toxicity limits the dose that can be given to mice and cats in vivo. We have experimentally ruled out various possibilities for the NQO1-independent cell death, and our experiments suggest that this toxicity is mediated by the reduction of DNQ by the one-electron reductase P450R. Herein we propose a comprehensive plan to widen the therapeutic index for DNQ and translate this drug class toward human clinical trials.
In Specific Aim 1 we use a combination of structure-activity relationships and in silico modeling to design 80 novel DNQ derivatives that are predicted to be worse substrates for P450R without compromising their NQO1 activity. These compounds will be moved through a tiered series of cell culture, and patient-derived xenograft (Specific Aim 2) experiments, with the top compounds being evaluated in pet cats with HNSCC in Specific Aim 3. Our goal is to have identified a derivative suitable for translation to human clinical trials by the end of the funding period. This tightly-focused, hypothesis-driven proposal could provide the first impactful targeted therapy for HNSCC; this would be a major breakthrough for this vastly underserved patient population.

Public Health Relevance

There are a lack of effective targeted therapies for head-and-neck cancers, and those patients with metastatic disease and bone invasion have a very poor prognosis. We have obtained substantial preliminary data showing that the overexpression of NQO1 can be an exploited in targeted therapy for head-and-neck cancer, using the compound DNQ and its derivatives. We now seek to use our innovative translational path to identify outstanding DNQ derivatives that can be advanced as a targeted therapies for head-and-neck cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE026836-01A1
Application #
9521199
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Wang, Chiayeng
Project Start
2018-08-15
Project End
2023-06-30
Budget Start
2018-08-15
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Genetics
Type
Organized Research Units
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820