| Summary: | Human papillomavirus-associated head and neck squamous cell carcinoma (HPV[+] HNSCC) is rapidly increasing in incidence and, in this regard, the effects of preventative HPV vaccines have yet to be realized. While HPV(+) HNSCC carries a more favorable prognosis than many other tumor types, a significant number of patients still experience treatment failure. Disease recurrence and metastasis are often fatal. Thus, factors that promote disease progression and underlie aggressive tumor phenotypes must be identified, and, most importantly, novel therapeutic approaches must be developed. Interestingly, β-adrenergic signaling plays a tumorigenic role in several cancer types and β-adrenergic antagonists (β-blockers) have recently garnered interest as anti-cancer agents. Herein, we identify increased β2-adrenergic receptor (β2AR) expression in an aggressive, recurrent/metastatic model of HPV(+) HNSCC as compared to the primary tumor model from which it was derived. This led us to hypothesize that β2AR contributes to an aggressive disease phenotype in HPV(+) HNSCC and that β-blockers would serve as an effective therapeutic tool in this setting. Here, we show that propranolol, a non-selective β-blocker, significantly delays primary tumor growth and decreases metastatic burden in mice implanted with this aggressive tumor model. Additionally, genetic deletion studies indicate that the model’s aggressive phenotype is critically dependent on expression of β2AR. Importantly, we identify that these effects are associated with inhibition of tumor cell mitochondrial metabolism and show that propranolol-mediated perturbations in mitochondrial respiration render tumor cells more sensitive to glucose starvation. Thus, we further hypothesized that concurrent glycolytic inhibition would enhance the anti-cancer activity of propranolol. To this end, we have developed a novel, metabolism-targeting treatment combination in propranolol and dichloroacetate (DCA), a glycolytic inhibitor. This combination dramatically attenuates tumor cell metabolism, displays significant anti-cancer effects in vitro, and delays tumor growth in vivo. Together, these data provide support for further investigation into the therapeutic potential of propranolol in the setting of HPV(+) HNSCC, and suggest that its effectiveness may be improved through combination with other metabolism-targeting drugs. Importantly, as a clinically-available agent, propranolol has the potential for swift translation from the bench to the bedside.
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