Utilizing feline oral squamous cell carcinoma patients to develop NQO1-targeted therapy.
Animals
Antineoplastic Agents
/ pharmacology
Carcinoma, Squamous Cell
/ diagnosis
Cats
Combined Modality Therapy
Disease Management
Disease Models, Animal
Drug Evaluation, Preclinical
Humans
Immunohistochemistry
Mice
Molecular Targeted Therapy
Mouth Neoplasms
/ diagnosis
Mutation
NAD(P)H Dehydrogenase (Quinone)
/ antagonists & inhibitors
Polymorphism, Single Nucleotide
Tomography, X-Ray Computed
Treatment Outcome
Comparative oncology
Feline
NQO1
Preclinical
Targeted therapy
Journal
Neoplasia (New York, N.Y.)
ISSN: 1476-5586
Titre abrégé: Neoplasia
Pays: United States
ID NLM: 100886622
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
17
05
2021
accepted:
10
06
2021
pubmed:
12
7
2021
medline:
18
1
2022
entrez:
11
7
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34246985
pii: S1476-5586(21)00049-X
doi: 10.1016/j.neo.2021.06.008
pmc: PMC8274297
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
NAD(P)H Dehydrogenase (Quinone)
EC 1.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
811-822Subventions
Organisme : NCI NIH HHS
ID : F99 CA253731
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE026836
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM136629
Pays : United States
Informations de copyright
Copyright © 2021. Published by Elsevier Inc.
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