Oral squamous cell carcinoma (OSCC), which accounts for the majority of head and neck cancers. Treatment for OSCC frequently involves a combination of surgery, radiotherapy, and chemotherapy. However, resistance to therapy complicates treatment, and the 5-year survival rate remains at ~65 percent. Understanding contributors to disease progression and treatment resistance is needed to promote patient outcomes. We propose here to study a potential molecular regulator of OSCC. Lysine-specific demethylase 1 (LSD1) is an amine oxidase with demethylase activity and has been implicated in maintaining the undifferentiated state of cancer-initiating cells. Our preliminary studies showed that LSD1 knockdown in HSC- 3 implanted orthotopic tumors attenuates tumor growth and metastasis in mouse models, whereas overexpression of LSD1 promotes it. Small molecule inhibitors (e.g., GSK-LSD1) of LSD1 attenuate disease in patient-derived xenografts (PDXs), EGFR-induced signaling, and pro-oncogenic gene (MMP13, LOXL4 and PD-L1). Microarrays followed by gene set enrichment analysis also showed that GSK-LSD1 inhibits the key mediators of EGFR signaling pathways. We hypothesize that conditional epithelial cell-specific deletion of LSD1 in the oral cavity attenuates epithelial OSCC progression and metastasis by reducing EGFR induced oncogenic signaling network to promote specific target genes. Further, we postulate that GSK-LSD1 in combination with immunotherapy or chemotherapy completely attenuates OSCC.
The specific aims of the study are to 1) determine if endogenous LSD1 is a key activator of specific target genes in murine 4NQO OSCC mouse model, and 2) determine if GSK-LSD1 sensitizes OSCC to chemotherapy or immunotherapy in PDOX and 4NQO mouse models by inhibiting EGFR, c-Myc, and PD-L1 signaling pathways. In vitro, ex-vivo, and in vivo approaches as well as microarrays and next- generation sequencing will be employed to address the proposed aims. LSD1 inhibitors could prove useful for OSCC immunotherapy and in personalized combination therapies. Thus, this study has a strong translational potential to identify LSD1 as a novel druggable target and its potential for anti-OSCC monotherapy and combination therapies.

Public Health Relevance

Oral cancer represents a significant societal burden. In this project, we propose to identify the key underlying causes of oral cancer by investigating changes in the chromatin environment brought about by an enzyme, lysine-specific demethylase 1 (LSD1). We anticipate that this study will increase knowledge about the biology of oral cancer, a synergistic combination of effective therapy and lead to the development of novel treatment strategies for this pernicious disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DE026892-02
Application #
9766270
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Wang, Chiayeng
Project Start
2018-09-01
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston University
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118