Oral squamous cell carcinoma (OSCC), or oral cancer, accounts for the majority of head and neck cancers. Resistance to therapy is a challenge, and 5-year survival rate remains at ~50 percent. Lysine-specific demethylase 1 (LSD1) plays a crucial role in controlling cell homeostasis in health and disease. LSD1 is elevated in oral cancer and promotes metastasis and correlates with poor prognosis. LSD1 is a nuclear histone demethylase that has been implicated in maintaining the undifferentiated state of cancer-initiating stem cells and promoting OSCC. Large dataset analysis showed that genetic alterations, including upregulation of LSD1, are seen in clinical cancers including OSCC. This study aims to evaluate the unknown mechanism of LSD1 and determine if pharmacologic inhibition of LSD1 has preventative and/or therapeutic applications for OSCC. This study used the 4NQO mouse model to induce OSCC in mice and split the mice into 8 treatment groups. Each group received a different immunotherapy treatment (SP2509, Verteporfin, anti PD-1 and anti PD-L1 alone and in combination). Our results have shown that LSD1 inhibition reduces the development of gross pathologic lesions. LSD1 inhibition has also shown to cause differences in gene expression in preneoplasia and OSCC, attenuating many genes that are part of the pro-oncogenic gene network (LSD1, YAP, EGFR), immune checkpoints (PD-1 and PD-L1), and Hippo signaling effectors (YAP, TAZ). Interestingly, LSD1 has shown a role in regulating the immune microenvironment and promoting antitumor immunity, which led us to investigate LSD1 in combination with immune checkpoint antibodies (anti PD-1 and anti PD-L1). Our results show that LSD1 sensitizes to anti-PD-1 and anti-PD-L1 antibodies to treat mouse tongue OSCC. Thus, we showed for the first time that blocking LSD1 inhibits preneoplasia and OSCC feed-forward loop, which could have implications in OSCC prevention, chemo- and immunotherapeutic combinations.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/46497 |
| Date | 25 July 2023 |
| Creators | Diny, Michael David |
| Contributors | Bias, Manish, Chogle, Sami |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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