Abstract
A paucity of advances in the development of novel therapeutic agents for squamous cell carcinomas of the head and neck, oral cavity (OSCC) and oropharynx, has stagnated disease free survival rates over the past two decades. Although immunotherapies targeted against checkpoint inhibitors such as PD-1 or CTLA-4 are just now entering the clinic for late stage disease with regularity the median improvement in overall survival is only about three months. There is an urgent unmet clinical need to identify new therapies that can be used alone or in combination with current approaches to increase survival by more than a few months. Activation of the apoptotic arm of the unfolded response (UPR) with small molecules and natural products has recently been demonstrated to be a productive approach in pre-clinical models of OSCC and several other cancers. The aim of current study was to perform a high throughput screen (HTS) with a diverse chemical library to identify compounds that could induce CHOP, a component of the apoptotic arm of the UPR. Disulfiram (DSF, also known as Antabuse) the well-known aversion therapy used to treat chronic alcoholism emerged as a hit that could generate reactive oxygen species, activate the UPR and apoptosis and reduce proliferation in OSCC cell cultures and xenografts. A panel of murine embryonic fibroblasts null for key UPR intermediates (e.g., Chop and Atf4) was resistant to DSF suggesting that an intact UPR is a key element of the mechanism regulating the antiproliferative effects of DSF.
Highlights
The Oral Cancer Foundation (OCF) has accurately predicted the annual incidence of oral (OSCC) and oropharyngeal cancer in the United States since 2002
We previously reported a productive high throughput screen (HTS) strategy used to discover small molecules and natural products that activated the apoptotic arm of the unfolded protein response (UPR) [25]
Williams prognosticated the potential of DSF to be used as a treatment for chronic alcoholism, noting that in the absence of ethanol the compound was quite benign but that the mechanism of action was unknown
Summary
The Oral Cancer Foundation (OCF) has accurately predicted the annual incidence of oral (OSCC) and oropharyngeal cancer in the United States since 2002. OCF anticipates that 2019 will see 50,000 new cases with about 10,000 deaths, substantially higher than in 2000 when the expected number was ~30,000 and had been unchanged for the previous two decades [1]. The high morbidity and mortality associated with OSCC are bolstered by the fact that approximately 60% of patients present with late stage disease. Promising clinical trials in 2016 and 2017 saw the introduction of immune modulating checkpoint inhibitors to the arsenal of FDA approved compounds for late stage and recurrent head and neck cancer these compounds are not yet approved for OSCC and there is an urgent unmet clinical need to find new approaches for patients afflicted with this devastating disease
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
