Dataset Information

Utilizing feline oral squamous cell carcinoma patients to develop NQO1-targeted therapy.

ABSTRACT: Developing effective therapies for the treatment of advanced head-and-neck squamous cell carcinoma (HNSCC) remains a major challenge, and there is a limited landscape of effective targeted therapies on the horizon. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a 2-electron reductase that is overexpressed in HNSCC and presents as a promising target for the treatment of HNSCC. Current NQO1-targeted drugs are hindered by their poor oxidative tolerability in human patients, underscoring a need for better preclinical screening for oxidative toxicities for NQO1-bioactivated small molecules. Herein, we describe our work to include felines and feline oral squamous cell carcinoma (FOSCC) patients in the preclinical assessment process to prioritize lead compounds with increased tolerability and efficacy prior to full human translation. Specifically, our data demonstrate that IB-DNQ, an NQO1-targeted small molecule, is well-tolerated in FOSCC patients and shows promising initial efficacy against FOSCC tumors in proof-of-concept single agent and radiotherapy combination cohorts. Furthermore, FOSCC tumors are amenable to evaluating a variety of target-inducible couplet hypotheses, evidenced herein with modulation of NQO1 levels with palliative radiotherapy. The use of felines and their naturally-occurring tumors provide an intriguing, often underutilized tool for preclinical drug development for NQO1-targeted approaches and has broader applications for the evaluation of other anticancer strategies.

SUBMITTER: Lundberg AP

PROVIDER: S-EPMC8274297 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Utilizing feline oral squamous cell carcinoma patients to develop NQO1-targeted therapy.

Lundberg Alycen P AP Boudreau Matthew W MW Selting Kim A KA Chatkewitz Lindsay E LE Samuelson Jonathan J Francis Joshua M JM Parkinson Elizabeth I EI Barger Anne M AM Hergenrother Paul J PJ Fan Timothy M TM

Neoplasia (New York, N.Y.) 20210708 8

Developing effective therapies for the treatment of advanced head-and-neck squamous cell carcinoma (HNSCC) remains a major challenge, and there is a limited landscape of effective targeted therapies on the horizon. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a 2-electron reductase that is overexpressed in HNSCC and presents as a promising target for the treatment of HNSCC. Current NQO1-targeted drugs are hindered by their poor oxidative tolerability in human patients, underscoring a need for bett ...[more]

PMID: 34246985

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Project description:Feline oral squamous cell carcinoma (FOSCC) is the most common oral neoplasia in cats. This malignant tumor is locally invasive, has a high mortality rate, and its etiology is not yet known. In humans, head and neck squamous cell carcinoma is associated with tobacco smoke, alcohol consumption, and human papillomavirus infection. Herein, a critical review about the potential etiologic factors of FOSCC was performed, considering publications between 2000 and 2022, aiming to synthesize all available scientific evidence regarding this issue. Recommendations of the PRISMA statement and the Cochrane Collaboration were followed and the PubMed database searched by using the MeSH terms MeSH terms "oral", "mouth", "lingual", "labial", "gingiva", "carcinoma", "squamous", and "feline". The selection process for eligible studies was based on specific inclusion and exclusion criteria and the quality of the studies assessed. The initial search resulted in 553 publications, with only 26 of these being included in the review. Sixteen studies were related to viral etiology and nine related to environmental factors such as exposure to tobacco smoke, ectoparasitic products, and the presence of oral comorbidities. When evaluated, feline papillomavirus was detected in 16.2% of samples of FOSCC. In the three studies focused on exposure to tobacco smoke, 35.2% (30/85) of cats with FOSCC had a history of this exposure. The consumption of canned food and the use of deworming collars were associated, in only one publication, with a risk of neoplasia increased by 4.7 and 5.3 times, respectively. Among 485 cats with FOSCC, 6.4% had dental and oral pathology (i.e., periodontal disease or feline chronic gingivostomatitis). The present study demonstrates that the available evidence on the etiology of FOSCC is still limited, however, there has been an increasing interest on this topic. To better understand the role of the possible etiological factors of this aggressive disease, and model for its human counterpart, large, prospective multi-institutional studies are needed.

Project description:Squamous cell carcinoma is the most common malignant oral tumor in cats. The late presentation is one of the factors contributing to the detrimental prognosis of this disease. The immunohistochemical expression of the p53 tumor suppressor protein has been reported in 24% to 65% of feline oral squamous cell carcinomas, but no study has systematically evaluated in this tumor the presence of p53 encoding gene (TP53) mutations. The aim of this retrospective study was to determine whether p53 immunohistochemistry accurately reflects the mutational status of the TP53 gene in feline oral squamous cell carcinoma. Additionally, the prevalence of p53 dysregulation in feline oral squamous cell carcinoma was compared with that of feline non-neoplastic oral mucosa, in order to investigate the relevance of these dysregulations in cancer development. The association between p53 dysregulations and exposure to environmental tobacco smoke and tumor characteristics was further assessed. Twenty-six incisional biopsies of oral squamous cell carcinomas and 10 cases each of lingual eosinophilic granuloma, chronic gingivostomatitis and normal oral mucosa were included in the study. Eighteen squamous cell carcinomas (69%) expressed p53 and 18 had mutations in exons 5-8 of TP53. The agreement between immunohistochemistry and mutation analysis was 77%. None of non-neoplastic oral mucosa samples had a positive immunohistochemical staining, while one case each of eosinophilic granuloma and chronic gingivostomatitis harbored TP53 mutations. Unlike previously hypothesized, p53 dysregulations were not associated with exposure to environmental tobacco smoke. These results suggest an important role of p53 in feline oral tumorigenesis. Additionally, the immunohistochemical detection of p53 expression appears to reflect the presence of TP53 mutations in the majority of cases. It remains to be determined if the screening for p53 dysregulations, alone or in association with other markers, can eventually contribute to the early detection of this devastating disease.

Dataset Information

Utilizing feline oral squamous cell carcinoma patients to develop NQO1-targeted therapy.

Publications

Utilizing feline oral squamous cell carcinoma patients to develop NQO1-targeted therapy.

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