Salivary gland cancer stem cells

唾液腺癌干细胞

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要问题：粘液表皮样癌（MEC）是最常见的恶性唾液腺癌。 MEC 的治疗方法仍然是根治性手术和放疗（在选定的病例中），因为尚未进行全身治疗经测试，目前的治疗策略通常与高发病率相关，晚期疾病患者生活质量差、肿瘤复发频繁、5年生存率低。理由：肿瘤的无情生长、对细胞毒治疗的抵抗和肿瘤复发的高发生率是 MEC 治疗中的主要挑战我们的小组证明 MEC 进展是由相对介导的。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更新，此处称为癌症干细胞样细胞 (CSC) 在 MEC 中，癌症干性由具有高水平的细胞表现出来。乙醛脱氢酶 (ALDH) 活性和高 CD44 表达（ALDHhighCD44high 细胞）。令人惊讶的是，细胞毒性药物不仅不会杀死 CSC，而且实际上会诱导 CSC。在我们寻找 MEC CSC 的可靶向脆弱性的过程中，我们进行了以下观察：A) 通过治疗抑制介导的 MEC CSC 分数的减少 mTOR 或 MDM2-p53 信号传导与 Bmi-1 表达下调相关 B) Bmi-1 是。这些观察结果表明 Bmi-1 可能发挥重要作用。在 MEC CSC 中，Bmi-1 是多梳抑制复合物的一个组成部分。 1 (PRC1) 作为干细胞自我更新的关键调节因子，但是 Bmi-1 对 MEC 的影响。值得注意的是，最近在卵巢癌患者中进行的临床试验。和儿科神经胶质瘤正在探索一类新型 Bmi-1 小分子抑制剂的安全性/有效性。然而，尚不清楚 Bmi-1 的治疗性抑制是否足以克服 Bmi-1 的内在耐药性。 MEC CSCs 到细胞毒性剂在这里，我们建议结合使用以下方法进行机制和转化研究。遗传和药理学方法来了解 Bmi-1 的功能及其治疗潜力靶向 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”。为了解决这个假设，我们提出以下具体目标：S.A.#1：定义 Bmi-1 的功能 MEC 肿瘤发生。S.A.#2：确定 Bmi-1 治疗抑制对 MEC 干性和肿瘤的影响 S.A.#3：确定抗 CSC 策略（Bmi-1 抑制）与抗批量药物相结合的效果。在耐药 MEC 异种移植模型中进行的临床前试验中的细胞肿瘤策略（细胞毒性治疗）。意义：这项工作将开始确定 Bmi-1 抑制剂直接靶向 CSC 对我们的长期目标是开发一种基于机制的疗法来预防肿瘤。复发并提高 MEC 患者的生存率和生活质量。可能与其他类型的化疗耐药腺体恶性肿瘤患者的治疗有关。