Salivary duct carcinoma (SDC) is a rare, aggressive type of salivary gland cancer that has many similarities to apocrine breast and prostate cancer, including high expression of androgen receptor (AR) and AR-regulated genes. Anti-androgen therapies (AAT) have been proposed as potential therapeutic options for SDC patients with aggressive disease. However, early clinical trial data indicates that only a subset of SDC patients responds to AAT, and the presence of AAT resistance mechanisms in untreated tumors suggests that durable long-term responses to AAT are unlikely for most SDC patients. Thus, new and effective therapeutic approaches for SDC are urgently needed.

FOXA1 is a nuclear protein required for AR-regulated gene expression and tumor growth/survival in apocrine breast and prostate cancer. FOXA1 expression is also strongly correlated with AR expression in SDC, and subsets of these tumors harbor FOXA1 gene alterations that have previously been shown to enhance AR-regulated gene expression in prostate cancer. Taken together, these data implicate FOXA1 as a critical regulator of AR-signaling in SDC; however, FOXA1 itself is not directly targetable. Intriguingly, the nuclear protein LSD1 regulates FOXA1 activity in prostate cancer, and the LSD1 inhibitor GSK2879552 has been shown to disrupt FOXA1-dependent AR signaling and tumor growth/survival.

Therefore, we hypothesize that LSD1 and FOXA1 co-regulate AR signaling in SDC, and targeting of FOXA1 via LSD1 inhibition represents a novel therapeutic approach for these aggressive tumors. To address this hypothesis, we will employ cutting-edge molecular techniques to characterize the role of FOXA1 and LSD1 in SDC biology and novel patient-derived tumor models to assess the therapeutic potential of the LSD1 inhibitor GSK2879552 for SDC patients with aggressive disease.

This proposed research directly addresses three Fiscal Year 2020 Rare Cancer Research Program Focus Areas: (1) Biology and Etiology, (2) Research Model, and (3) Therapy. This research will be most applicable to SDC patients who require systemic treatment for metastatic disease. The short-term impact (1-2 years) of this work is nomination of FOXA1 as an indirect therapeutic target via LSD1 inhibition for SDC patients, which could provide the necessary evidence for future SDC clinical trials (5-10 years). Thus, the potential long-term impact (>10 years) of this work is improved clinical outcomes for patients with this rare type of aggressive salivary gland cancer. In addition, the generation of novel patient-derived SDC models for future study may help researchers better understand the biology of these rare tumors and uncover new therapeutic targets to improve clinical outcomes for SDC patients.