Neoplasia (New York, N.Y.), 2021-08, Vol.23 (8), p.811-822
2021
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Details
- Autor(en) / Beteiligte
- Titel
- Utilizing feline oral squamous cell carcinoma patients to develop NQO1-targeted therapy
- Ist Teil von
- Neoplasia (New York, N.Y.), 2021-08, Vol.23 (8), p.811-822
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2021
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1476-5586, 1522-8002eISSN: 1476-5586DOI: 10.1016/j.neo.2021.06.008Titel-ID: cdi_doaj_primary_oai_doaj_org_article_65baeeaccc594d50a1f1c47686eda0a4
- Format
- –
- Schlagworte
- Animals, Antineoplastic Agents - pharmacology, Carcinoma, Squamous Cell - diagnosis, Carcinoma, Squamous Cell - drug therapy, Carcinoma, Squamous Cell - etiology, Carcinoma, Squamous Cell - metabolism, Cats, Combined Modality Therapy, Comparative oncology, Disease Management, Disease Models, Animal, Drug Evaluation, Preclinical, Feline, Humans, Immunohistochemistry, Mice, Molecular Targeted Therapy, Mouth Neoplasms - diagnosis, Mouth Neoplasms - drug therapy, Mouth Neoplasms - etiology, Mouth Neoplasms - metabolism, Mutation, NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors, NAD(P)H Dehydrogenase (Quinone) - genetics, NAD(P)H Dehydrogenase (Quinone) - metabolism, NQO1, Original Research, Polymorphism, Single Nucleotide, Preclinical, Targeted therapy, Tomography, X-Ray Computed, Treatment Outcome