Salivary gland cancer stem cells

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PROJECT SUMMARY/ABSTRACT The Problem: Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland cancer. The treatment for MEC still is radical surgery and radiotherapy (in selected cases), as no systemic therapy has been approved for this cancer. Consequently, current treatment strategies are typically associated with high morbidity, poor quality of life, frequent tumor relapse and low 5-year survival rates for patients with advanced disease. Rationale: Relentless tumor growth, resistance to cytotoxic therapy and high incidence of tumor relapse are the major challenges in MEC treatment. Our group demonstrated that MEC progression is mediated by a relatively small population of tumor-initiating cells that exhibit a stem-like state characterized by multipotency and self- renewal, named here cancer stem-like cells (CSC). In MEC, cancer stemness is exhibited by cells with high aldehyde dehydrogenase (ALDH) activity and high CD44 expression (ALDHhighCD44high cells). These cells are uniquely resistant to cytotoxic therapy. Surprisingly, cytotoxic agents not only do not kill CSCs, but actually induce cancer stemness while inhibiting tumor growth. In our search for a targetable vulnerability of MEC CSCs, we made the following observations: A) The decrease in MEC CSC fraction mediated by therapeutic inhibition of either mTOR or MDM2-p53 signaling is associated with downregulation of Bmi-1 expression. B) Bmi-1 is constitutively upregulated by MEC CSCs. These observations suggested that Bmi-1 may play a significant role in MEC CSCs that could be exploited therapeutically. Bmi-1 is a component of the polycomb repressive complex- 1 (PRC1) that functions as a critical regulator of stem cell self-renewal. However, Bmi-1’s effect on MEC tumorigenesis and cancer stemness are unknown. Notably, recent clinical trials in patients with ovarian cancer and pediatric glioma are exploring the safety/efficacy of a novel class of small molecule inhibitors of Bmi-1. However, it is unclear whether therapeutic inhibition of Bmi-1 is sufficient to overcome the intrinsic resistance of MEC CSCs to cytotoxic agents. Here, we propose mechanistic and translational studies using a combination of genetic and pharmacologic approaches to understand the function of Bmi-1 and the therapeutic potential of targeting Bmi-1 in MEC. Our overall hypothesis is “Bmi-1 drives tumorigenesis and chemoresistance in MEC”. To address this hypothesis, we propose the following specific aims: S.A.#1: To define the function of Bmi-1 on MEC tumorigenesis. S.A.#2: To define the effect of therapeutic inhibition of Bmi-1 on MEC stemness and tumor relapse. S.A.#3: To determine the effect of an anti-CSC strategy (Bmi-1 inhibition) combined with an anti-bulk tumor cell strategy (cytotoxic therapy) in preclinical trials conducted in xenograft models of resistant MEC. Significance: This work will begin to define the effect of direct targeting of CSCs with Bmi-1 inhibitors on the treatment outcome for MEC. Our long-term goal is to develop a mechanism-based therapy that prevents tumor relapse and that improves the survival and quality of life of patients with MEC. Successful outcomes of this study might be pertinent to the treatment of patients with other types of chemoresistant glandular malignancies.