Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Oral cancer is a highly aggressive and devastating malignancy with a poor prognosis at the advanced stage, resulting in ~300,000 deaths each year worldwide. Currently no effective targeted therapies are available for oral cancer; thus, there remains an urgent need to develop new therapeutic options to prevent and treat oral cancer. ADP-ribosylation factor 1 (Arf1) is a member of the Ras superfamily of small GTPases playing a major role in vesicular trafficking. Arf1 is highly expressed and hyperactivated in oral cancer, where it functions as an oncogenic driver to favor cancer development and progression. As a critical step in the functional cycle of Arf GTPases is their activation by guanine-nucleotide exchange factors (ArfGEFs), interrupting the protein-protein interaction between Arf1 and its specific Arf1GEFs remains an attractive strategy to block Arf1 signaling. Recently, we have discovered a novel Arf1 inhibitory compound 10b (AI10b) that can structurally mimic the intrinsic autoinhibitory segment of Arf1GEFs to selectively block Arf1 activation without affecting other Arf family members. AI10b exhibits a superior anticancer activity in oral cancer cells than other existing Arf1 inhibitors with no apparent toxicity against normal oral keratinocytes, holding promise to be developed into a safe and effective targeted therapy for oral cancer patients. Intriguingly, AI10b induces oral cancer cell pyroptosis, a highly immunogenic form of cell death, and this process requires the cleavage of gasdermin D (GSDMD). Moreover, AI10b-mediated regression of GSDMD-positive (GSDMD+) oral tumors is markedly impaired in T cell-deficient TCRαKO mice and CD8+ T cell-depleted C57BL/6 mice, suggesting the requirement of CD8+ T cells for a prolonged immune response to AI10b. These novel and significant findings inform our central hypothesis that AI10b can, in addition to its direct cytotoxic effect, trigger host antitumor immunity to eliminate oral tumors. To test this, there are three Specific Aims: (1) to elucidate the mechanisms underlying AI10b-mediated pyroptosis in oral tumors; (2) to dissect the mechanisms by which AI10b-induced oral cancer cell pyroptosis potentiates antitumor CD8+ T cell immunity; and (3) to develop GSDMD-based differential strategies to augment the efficacy of AI10b in oral tumors. We will integrate cutting-edge techniques in cancer biology and immunology to attain our objectives, with a long-term goal to improve the therapeutic efficacy of targeted oral cancer therapy. The success of this project would be a breakthrough in discovering an impactful treatment that can preferentially target oral or other tumors with hyperactive Arf1 signaling.
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