Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, resulting in over 14,600 deaths each year in the United States alone. HNSCC is associated with human papillomavirus (HPV) infection, and tobacco use and abusive alcohol intake. Recent revolutionary immunotherapy approaches have changed the landscape of treatment options in HNSCC. However, less than 20% of HNSCC patients respond to FDA-approved anti-PD1 immune checkpoint blockade (ICB) (pembrolizumab and nivolumab), often not leading to durable responses. This highlights the unmet need to identify novel therapeutic options and biomarkers predicting more favorable response to maximize the efficacy of immune-oncology (IO) strategies for HNSCC treatment. Glutamine is a conditionally essential amino acid for rapidly proliferating cancer cells making glutamine pathway inhibition an attractive approach for anti-cancer therapy. Treatment with the glutamine antagonist (DRP-104), which irreversibly inhibits all known enzymes involved in glutamine metabolism within the tumor, resulted in metabolically halted cell growth in vitro in a large panel of cell lines (n=8) representing the spectra of HPV- and HPV+ HNSCC, with an IC50 of 0.2-25uM, Interestingly, HNSCC cells bearing genetic alterations in PIK3CA/PTEN were significantly more sensitive to glutamine antagonism in comparison to unaltered HNSCC cells. The dependence of glutamine in HNSCC growth and the increased sensitivity of PIK3CA/PTEN aberrant cells was also observed in orosphere assays and 6 distinct HNSCC tumor xenografts in NOD SCID mice. We next investigated the efficacy of glutamine suppression in the context of an intact immune system, taking advantage of new syngeneic HNSCC model system, 4MOSC and MOC1. Specifically, we recently developed orthotopic syngeneic mouse models, 4MOSC, reflecting human tobacco-related HNSCC genomic alterations and mutational landscape (Wang et al., Nature Comm 2019), while MOC1 is a DMBA-induced mouse HNSCC cell line grown in the subcutaneous flank of mice (Judd et al. Cancer Res 2011). Monotherapy administration of DRP- 104 (1.4mg/kg) was potent as a monotherapy in all three syngeneic HNSCC models. We also observed a trend of increased sensitivity when DRP-104 was combined with anti-PD-1 therapy. Our data suggest that broad glutamine antagonism using DRP-104 has therapeutic potential in HNSCC by both dismantling cancer metabolism and enhancing the anti-tumor immune response of immune checkpoint blockade. Clinical trials of DRP-104 are currently ongoing.

Citation Format: Michael Allevato, Yumi Yokoyama, Robert Wild, Silvio Gutkind. Halting head & neck squamous cell carcinoma progression by broadly targeting glutamine metabolic pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2339.