Salivary gland cancer stem cells

项目概要/摘要 问题：粘液表皮样癌（MEC）是最常见的恶性唾液腺癌。的 MEC的治疗仍然是根治性手术和放射治疗（在选定的病例中），因为尚未进行全身治疗 被批准用于治疗这种癌症因此，目前的治疗策略通常与高发病率相关， 晚期患者生活质量差，肿瘤复发频繁，5年生存率低。 基本原理：肿瘤的持续生长、对细胞毒性治疗的耐药性和肿瘤复发的高发生率是肿瘤复发的主要原因。 MEC治疗的主要挑战。我们的研究小组证明MEC的进展是由一个相对稳定的蛋白介导的。 一小群肿瘤起始细胞，表现出干细胞样状态，其特征是多能性和自我分化。 更新，在此命名为癌症干细胞样细胞（CSC）。在MEC中，癌症干细胞表现为高表达的细胞， 醛脱氢酶（ALDH）活性和高CD44表达（ALDHhighCD44high细胞）。这些细胞 对细胞毒疗法有独特的抵抗力。令人惊讶的是，细胞毒性剂不仅不杀死CSC，而且实际上诱导了CSC。 抑制肿瘤生长的同时抑制癌细胞增殖。在我们寻找MEC CSC的目标漏洞时，我们 A）MEC CSC分数的减少由MEC CSC的治疗性抑制介导， mTOR或MDM2-p53信号传导与Bmi-1表达的下调有关。B）Bmi-1是 在某些实施方案中，其由MEC CSC组成性上调。这些观察结果表明，Bmi-1可能发挥重要作用， 在MEC CSC中可以用于治疗。BMI-1是多梳抑制复合体的一个组成部分 1（PRC1），作为干细胞自我更新的关键调节因子。然而，Bmi-1对MEC的影响 肿瘤发生和癌的干性是未知的。值得注意的是，最近在卵巢癌患者中进行的临床试验 和小儿神经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Bmi-1的治疗性抑制是否足以克服Bmi-1的内在抗性。 MEC CSC与细胞毒性剂。在这里，我们提出了机制和翻译研究使用的组合， 遗传学和药理学方法来了解Bmi-1的功能和治疗潜力， 针对MEC中的Bmi-1。我们的总体假设是"Bmi-1驱动MEC中的肿瘤发生和化疗耐药性"。 为了解决这一假设，我们提出了以下具体目标：1：定义Bmi-1的功能 MEC肿瘤发生。S.A.编号2：确定Bmi-1的治疗性抑制对MEC干性和肿瘤的影响 复发S.A.编号3：确定抗CSC策略（Bmi-1抑制）与抗肿瘤药物组合的效果 在耐药MEC异种移植模型中进行的临床前试验中使用肿瘤细胞策略（细胞毒性疗法）。 意义：这项工作将开始以确定用Bmi-1抑制剂直接靶向CSC对肿瘤细胞增殖的影响。 MEC的治疗结果。我们的长期目标是开发一种基于机制的治疗方法， 复发，并提高MEC患者的生存率和生活质量。本研究的成功结果 可能与其他类型的耐药腺体恶性肿瘤患者的治疗有关。

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.