Abstract 1886: Targeting oral squamous cell carcinoma tumor microenvironment through simultaneous modulation of pattern recognition receptors and angiogenic factors using a synthetic polymer-based drug

Abstract

Abstract Squamous cell carcinomas (SCCs) are the dominant form of cancers of the upper aerodigestive tract. Main risk factors are smoking and human papilloma virus (HPV) infection. Despite the HPV vaccination efforts, the number of oropharyngeal cancers (OSCCs) has been steadily increasing especially in males. Standard of care primarily focuses on the surgical removal of cancerous tissues followed by chemoradiation therapy. However, the recurrence rate of OSCCs remains fairly high as the tumor frequently develops therapy resistance and more effective therapeutic regimens are needed. The chronic inflammatory state yet paradoxical immunosuppressive tumor microenvironment has been regarded as a cause of therapy resistance and suggested as a potential therapeutic target. Pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) contribute to pro-inflammatory tissue responses. TLR2 present in the OSCC tumor appears to play important roles in regulating immune responses and promoting pro-inflammatory tumor microenvironment. GM-1111 is a synthetic glycosaminoglycan-based anti-inflammatory molecule that potently inhibits PRRs such as TLR2 and NLRP3 inflammasome. In addition, GM-1111 inhibits multiple angiogenic molecules - CXCL12, VEGF, and FGF2. We hypothesized that GM-1111 might be able to reduce OSCC tumor growth by simultaneously disrupting pro-inflammatory as well as angiogenic signaling. To test this hypothesis, male CD1 nude mice bearing FaDu cell tumor in the back were treated with either (1) vehicle, (2) GM-1111 (30 mg/kg, q.d., s.c.), (3) vehicle with irradiation (2 Gy/day x 5 days), or (4) GM-1111 with irradiation 17 days. Established tumors grew in two phases from slow for the initial 7 days to fast growths during the remaining days. Irradiation- or drug-induced tumor regression was observable about 5 days after the last radiation therapy (day 10). Compared to the vehicle only (1) treatment group, GM-1111 treated animals (groups 1 vs. 2: p = 0.0032; groups 1 vs. 3: p < 0.0001; groups 1 vs. 4: p < 0.0001) demonstrated significantly reduced tumor growth. These results suggest that GM-1111 has a potential to reduce OSCC and further confirm our previous orthotopic human tongue SCC-25 cell xenograft study data. Citation Format: Won Yong Lee, Frida Ponthan, Stephen T. Sonis. Targeting oral squamous cell carcinoma tumor microenvironment through simultaneous modulation of pattern recognition receptors and angiogenic factors using a synthetic polymer-based drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1886.