Salivary gland cancer stem cells

项目摘要/摘要 问题：粘液表皮样癌(MEC)是最常见的恶性涎腺癌。这个 MEC的治疗仍然是根治性手术和放射治疗(在某些情况下)，因为没有系统的治疗。 被批准治疗这种癌症。因此，目前的治疗策略通常与高发病率有关， 晚期疾病患者生活质量差，肿瘤复发频繁，5年生存率低。 理论基础：肿瘤的持续生长、对细胞毒治疗的抵抗和肿瘤的高复发率是 MEC治疗中的主要挑战。我们的小组证明了MEC的进展是由一个相对 一小群肿瘤启动细胞，表现出干细胞样状态，其特征是多潜能和自我- 更新换代，这里命名为肿瘤干细胞样细胞(CSC)。在MEC中，高表达的细胞表现出癌症的干性 乙醛脱氢酶(ALDH)活性和CD44高表达(ALDHHighCD44High细胞)。这些细胞是 对细胞毒治疗具有独特的抵抗力。令人惊讶的是，细胞毒剂不仅不会杀死CSCs，反而会诱导 抑制肿瘤生长的同时抑制癌症的生长。在我们寻找MEC CSCs的目标漏洞时，我们 进行了以下观察：a)MEC CSC分数的降低由治疗抑制所介导 MTOR或MDM2-P53信号与BMI-1表达下调有关。B)BMI-1是 由MEC CSCs结构性上调。这些观察结果表明，BMI-1可能起着重要作用 在MEC CSCs中，可以用于治疗。Bmi-1是多梳抑制复合体的一个成分- 1(Prc1)，作为干细胞自我更新的关键调节因子。然而，体重指数-1‘S对微血管内皮细胞的影响 肿瘤的发生和癌症的干细胞是未知的。值得注意的是，最近对卵巢癌患者的临床试验 和儿童胶质瘤正在探索一类新的BMI-1小分子抑制剂的安全性/有效性。 然而，目前尚不清楚治疗性抑制BMI-1是否足以克服BMI-1的内在耐药性 MEC CSCs对细胞毒药物的作用。在这里，我们建议使用机械和翻译相结合的研究 遗传学和药理学方法了解BMI-1的功能和治疗高血压的潜力 在MEC中靶向BMI-1。我们的总体假设是“BMI-1驱动微血管内皮细胞的肿瘤发生和化疗耐药”。 为了解决这一假设，我们提出了以下具体目标：S.A.#1：定义BMI-1在 MEC肿瘤发生学。S.A.#2：确定治疗抑制BMI-1对MEC干细胞和肿瘤的影响 旧病复发。S.A.#3：确定抗CSC策略(BMI-1抑制)与抗Bulk联合的效果 在耐药微血管内皮细胞异种移植模型中进行的临床前试验中的肿瘤细胞策略(细胞毒治疗)。 意义：这项工作将开始定义BMI-1抑制剂直接靶向CSCs对 MEC的治疗结果。我们的长期目标是开发一种基于机制的预防肿瘤的疗法 复发，从而改善MEC患者的生存和生活质量。这项研究的成功结果 可能与治疗其他类型的化疗耐药性腺恶性肿瘤有关。

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.