Perivascular niche for salivary gland cancer stem cells and resistance to therapy

唾液腺癌干细胞的血管周围生态位和治疗耐药性

基本信息

批准号：
10180934
负责人：
Jacques Eduardo Nor
金额：
$ 36.81万
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 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180934
关键词：
Ablation Address Adult Affect Animal Model Antineoplastic Agents Apoptotic Applications Grants Body mass index CD44 gene Cell Fraction Cell Line Cell Survival Cells Child Clinical Management Clinical Trials Combined Modality Therapy Data Development Developmental Therapeutics Program Dose Enhancers Exhibits Experimental Models FDA approved FRAP1 gene Funding Goals Growth Human In Vitro Knowledge Link MDM2 gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of salivary gland Mediating Modeling Morbidity - disease rate Mucoepidermoid Carcinoma Mutation National Institute of Dental and Craniofacial Research Operative Surgical Procedures Oral Pathology Outcome Outcome Study Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Pilot Projects Population Positioning Attribute Process Quality of life Recurrence Research Research Design Resistance Role Safety Salivary Gland Neoplasms Signal Transduction Survival Rate TP53 gene Testing Therapeutic Therapeutic Effect United States National Institutes of Health Vertebral column Work Xenograft Model Xenograft procedure aldehyde dehydrogenases antitumor effect base cancer stem cell cancer type chemotherapy clinically relevant design effective therapy experience improved in vivo mTOR Inhibitor mTOR inhibition neoplastic cell new combination therapies novel novel therapeutics prevent self-renewal small molecule inhibitor stem cell biology stem-like cell targeted cancer therapy targeted treatment therapy resistant tumor tumor growth tumor xenograft tumorigenesis tumorigenic

项目摘要

The Problem: Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland cancer in adults and in children. Relentless growth and resistance to chemotherapy are hallmarks of MEC. Indeed, there is no FDA-approved drug for this cancer. Therefore, the primary treatment still is radical surgery, which is typically associated with high morbidity, poor quality of life, and an unacceptably low 5-year survival rate of 21- 25% for patients with stage II-IV MEC. Rationale: Lack of cell lines and animal models was identified by the NIH/NIDCR as a major roadblock to the discovery of new therapies for salivary gland cancer. In the 1st funding cycle, we generated and characterized the first panel of validated tumorigenic human MEC cell lines and xenograft tumor models (Warner et al., 2013). Using these models, we demonstrated that MEC follows the cancer stem cell hypothesis and that ALDH/CD44 identifies MEC cancer stem cells (Adams et al, 2015). Emerging evidence from other tumor types demonstrates that cancer stem cells are resistant to therapy and drive tumor recurrence, which are key challenges in the clinical management of patients with MEC. In an effort to develop an approach to overcome resistance to therapy, we focused our work on developing strategies targeting MEC cancer stem cells. We observed that the Akt-mTOR-S6K1 pathway is constitutively active in MEC cancer stem cells. In pilot studies, we showed that inhibition of mTOR with Temsirolimus results in significant decrease in the fraction of MEC cancer stem cells and inhibition of Bmi-1 (marker of self-renewal) in vivo. We have also investigated MDM2, an enhancer of tumor cell survival that is involved in the pathogenesis of MEC. We made the exciting observation that small molecule inhibitors of the MDM2-p53 interaction (e.g. MI- 773) ablate MEC cancer stem cells in vitro and in xenograft tumors. Interestingly, it has been shown that S6K1 regulates MDM2 protein stability, providing a mechanistic link between the mTOR pathway and MDM2. Our hypothesis is that therapeutic inhibition of mTOR and/or MDM2 ablates cancer stem cells and sensitizes mucoepidermoid carcinomas to chemotherapy. To address this hypothesis, we propose the following specific aims: S.A.#1: To define the effect of the mTOR pathway on the survival/self-renewal of cancer stem cells, and on the recurrence of mucoepidermoid carcinomas. S.A.#2: To define the effect of therapeutic inhibition of the MDM2-p53 interaction on the growth and recurrence of mucoepidermoid carcinomas. S.A.#3: To determine the effect of therapeutic inhibition of mTOR and/or MDM2 on the resistance of mucoepidermoid carcinomas to conventional chemotherapy (Cisplatin). Significance: This competing renewal builds upon a key discovery made in the 1st funding cycle, i.e. cancer stem cells drive MEC tumorigenesis. Here, our focus is on developing a mechanism-based therapy targeting MEC cancer stem cells for ablation with clinically relevant inhibitors of mTOR and/or MDM2-p53. As such, successful outcome of this work will provide support for a therapy that can quickly progress towards a clinical trial aiming at improving the survival of mucoepidermoid carcinoma patients.

问题：粘膜表皮类癌（MEC）是最常见的恶性唾液腺癌成人和儿童。不懈的生长和对化疗的耐药性是MEC的标志。确实，那里对于这种癌症，不是FDA批准的药物。因此，主要治疗仍然是根治性手术，通常与高发病率，生活质量差以及低5年的低5年生存率21-相关 II-IV期MEC患者25％。理由：缺乏细胞系和动物模型。 NIH/NIDCR是发现新的唾液腺癌疗法的主要障碍。在第一款资金中循环，我们生成并表征了第一个经过验证的肿瘤性人MEC细胞系和异种移植肿瘤模型（Warner等，2013）。使用这些模型，我们证明了MEC遵循癌症干细胞假设，ALDH/CD44鉴定了MEC癌症干细胞（Adams等，2015）。来自其他肿瘤类型的新兴证据表明，癌症干细胞对治疗和驱动肿瘤复发，这是MEC患者临床管理中的关键挑战。努力为了开发一种克服对治疗的抵抗的方法，我们将工作重点放在制定策略上靶向MEC癌干细胞。我们观察到Akt-MTOR-S6K1途径在组成性活动 MEC癌干细胞。在试点研究中，我们表明用Temsirolimus抑制MTOR导致 MEC癌症干细胞的分数显着降低并抑制BMI-1（自我更新的标记）体内。我们还研究了MDM2，这是一种参与发病机理的肿瘤细胞存活的增强子 MEC。我们对MDM2-P53相互作用的小分子抑制剂进行了令人兴奋的观察 773）在体外和异种移植肿瘤中消融MEC癌症干细胞。有趣的是，已经表明S6K1 调节MDM2蛋白稳定性，在MTOR途径和MDM2之间提供机械联系。我们的假设是对MTOR和/或MDM2的治疗抑制消化了癌症干细胞并敏感粘膜表皮类癌对化学疗法。为了解决这一假设，我们提出以下特定目的：S.A。＃1：定义MTOR途径对癌症干细胞生存/自我更新的影响，以及关于粘膜表皮癌的复发。 S.A.＃2：定义对治疗性抑制的影响 MDM2-P53关于粘膜表皮类癌的生长和复发的相互作用。 S.A.＃3：确定 MTOR和/或MDM2的治疗性抑制对粘膜外皮类癌对抗性的影响常规化学疗法（顺铂）。意义：这种竞争的更新建立在关键发现的基础上在第一个资金周期中进行的，即癌症干细胞驱动MEC肿瘤发生。在这里，我们的重点是发展一种基于机制的治疗，靶向MEC癌症干细胞，以消融，以临床相关的抑制剂 MTOR和/或MDM2-P53。因此，这项工作的成功结果将为可以提供支持旨在改善粘膜表皮癌患者生存的临床试验迅速发展。