Salivary gland cancer stem cells

唾液腺癌干细胞

• 批准号: 10581665
• 负责人: Jacques Eduardo Nor
• 金额: $ 37.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-10 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581665
• 关键词: Ablation; Acute Myelocytic Leukemia; Address; Affect; Apoptosis; CD44 gene; Cell Fraction; Cell Line; Cells; Chemoresistance; Childhood Glioma; Cisplatin; Clinical Trials; Cytotoxic Chemotherapy; Cytotoxic agent; Down-Regulation; Endowment; Excision; Exclusion; Exhibits; FRAP1 gene; Funding; Genetic; Goals; Head and Neck Squamous Cell Carcinoma; Human; Incidence; MDM2 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of salivary gland; Mediating; Morbidity - disease rate; Mucoepidermoid Carcinoma; Mutation; Names; Neoplasm Metastasis; Operative Surgical Procedures; Oral; Outcome; Outcome Study; PRC1 Protein; Pathway interactions; Patients; Phase I/II Trial; Platinum; Play; Population; Postoperative Period; Pre-Clinical Model; Quality of life; Radiation; Radiation therapy; Recurrence; Relapse; Reporting; Research; Resistance; Role; Safety; Salivary Gland Mucoepidermoid Carcinoma; Signal Transduction; Survival Rate; Systemic Therapy; TP53 gene; Testing; Therapeutic; Therapeutic Effect; Treatment outcome; Tumor Debulking; Up-Regulation; Work; Xenograft Model; advanced disease; aldehyde dehydrogenases; anti-cancer; antitumor effect; cancer stem cell; carcinogenesis; chemotherapy; clinically relevant; conventional therapy; cytotoxic; exome sequencing; improved; inhibitor; mTOR inhibition; mortality; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; overexpression; pharmacologic; preclinical trial; prevent; refractory cancer; safety testing; self-renewal; small molecule inhibitor; standard care; stem; stem cell self renewal; stem-like cell; stemness; success; targeted treatment; translational study; treatment response; treatment strategy; tumor; tumor growth; tumor initiation; tumorigenesis; tumorigenic

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.

项目摘要/摘要 问题：粘膜外皮类癌（MEC）是最常见的恶性唾液腺癌。这 MEC的治疗仍然是根治性手术和放疗（在某些情况下），因为没有全身治疗 批准了这种癌症。因此，当前的治疗策略通常与高发病率有关 患有晚期疾病的患者的生活质量差，经常肿瘤缓解和低5年生存率。 理由：无情的肿瘤生长，对细胞毒性疗法的抵抗力和肿瘤救济的高入射 MEC治疗中的主要挑战。我们的小组证明MEC的进展是由相对较大的 存在以多能力和自我为特征的茎状肿瘤发射细胞的少数人群 更新，此处命名为癌症干细胞（CSC）。在MEC中，癌症的癌症暴露于具有高的细胞 醛脱氢酶（ALDH）活性和高CD44表达（AldhhhighCD44高细胞）。这些细胞是 令人惊讶的是，细胞毒性剂不仅不杀死CSC，而且实际上会诱导 癌症，同时抑制肿瘤生长。在我们寻找MEC CSC的目标漏洞时，我们 进行以下观察：a）通过治疗性抑制介导的MEC CSC分数的降低 MTOR或MDM2-P53信号传导都与BMI-1表达的下调有关。 b）BMI-1是 由MEC CSC进行组成性更新。这些观察结果表明，BMI-1可能发挥重要作用 在可以热探索的MEC CSC中。 BMI-1是Polycomb反射复合物的组成部分 1（PRC1）起着干细胞自我更新的关键调节剂。但是，BMI-1对MEC的影响 肿瘤发生和癌症尚不清楚。值得注意的是，最近在卵巢癌患者中进行的临床试验 小儿神经胶质瘤正在探索BMI-1的新型小分子抑制剂的安全/功效。 但是，尚不清楚BMI-1的治疗性抑制是否足以克服 MEC CSCS到细胞毒性剂。在这里，我们提出了使用的机械和翻译研究 了解BMI-1功能和治疗潜力的遗传和药理方法 靶向MEC中的BMI-1。我们的总体假设是“ BMI-1驱动MEC的肿瘤发生和化学抗性”。 为了解决这一假设，我们提出了以下特定目的：S.A.＃1：定义BMI-1的功能 MEC肿瘤发生。 S.A.＃2：定义理论抑制BMI-1对MEC茎和肿瘤的影响 复发。 S.A.＃3：确定抗CSC策略（BMI-1抑制）的影响 在抗性MEC的异种移植模型中进行的临床前试验中的肿瘤细胞策略（细胞毒性疗法）。 意义：这项工作将开始定义用BMI-1抑制剂直接靶向CSC对 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，以防止肿瘤 复发并改善了MEC患者的生存和生活质量。这项研究的成功结果 可能与其他类型的化学腺体恶性肿瘤患者的治疗有关。