Abstract IA020: Targeting mTOR signaling in oral premalignant lesions: From bench to clinic and back

Despite encouraging recent results from novel treatment options, such as immunotherapy, for head and neck squamous cell carcinoma (HNSCC), limited progress has been made in improving outcomes for most patients. Prevention and early detection are key to improving the prognosis of HNSCC. Our team has focused on decoding the oncogenic signaling circuitries driving HNSCC initiation and progression, aimed at identifying novel druggable targets to treat and prevent this aggressive malignancy. These efforts led to the early discovery that persistent activation of PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in HNSCC, and that in turn, the overreliance on PI3K/mTOR for HNSCC initiation and progression can be exploited for therapeutic purposes. Evidence will presented that mTOR inhibition exerts a potent antitumor activity in HNSCC patients in a recently reported window of opportunity clinical trial (NCT01195922). Thus, mTOR inhibitors can be considered for the prevention of HNSCC development and for the treatment of existing HNSCC lesions. However, their safety profile and tolerability may hamper their potential long-term use for HNSCC prevention. In this regard, we have shown that the repurposed drug metformin, which is safely used by millions of type 2 diabetes patients, decreases mTOR signaling in HNSCC and displays potent chemopreventive activity in experimental oral premalignancy models. Based on these findings, we have conducted a Phase IIa Clinical Trial using metformin for HNSCC prevention (NCT02581137) in patients with oral premalignant lesions (OPL), which was recently completed. Metformin administration resulted in mTOR inhibition, and improvement in the histological severity of 60% of the OPLs, including a subset (17%) of patients that exhibited complete responses. Ongoing experimental and planned clinical studies will be presented, which may provide a mechanistic framework for the use of metformin as a precision preventive agent for HNSCC.

Citation Format: J. Silvio Gutkind. Targeting mTOR signaling in oral premalignant lesions: From bench to clinic and back [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA020.