Therapeutic Inhibition of MDM2/Bcl-2 in Pre-clinical Models of Adenoid Cystic Car

MDM2/Bcl-2 在腺样囊肿临床前模型中的治疗性抑制

基本信息

批准号：
8915672
负责人：
Jacques Eduardo Nor
金额：
$ 38.88万
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：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915672
关键词：
Address Adenoid Cystic Carcinoma Adenoidal structure Animal Model Anoikis Antibodies Apoptosis Apoptotic BCL2 gene Binding Bioluminescence Cell Death Cell Line Cells Cisplatin Clinical Management Clinical Trials Combined Modality Therapy Cultured Cells Data Development Developmental Therapeutics Program Diagnosis Drug Targeting Endothelial Cells Epitopes Evaluation Experimental Animal Model Exposure to Family member Gene Expression Profile Generations Goals Growth Human Immunodeficient Mouse In Vitro MDM2 gene Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of salivary gland Methods Modeling Monitor Morbidity - disease rate Mus Oncogene Proteins Oncogenic Operative Surgical Procedures Oral Pathology Outcome Outcome Study Pathway interactions Patients Pharmaceutical Preparations Phase I/II Trial Play Positioning Attribute Pre-Clinical Model Primary Neoplasm Proteins Quality of life Recurrence Research Research Personnel Resistance Role SCID Mice Seeds Series Signal Transduction Signaling Molecule Specimen Stromal Cells Survival Rate Testing Therapeutic Therapeutic Effect Therapeutic Studies Time Transplantation Tumor Angiogenesis United States Vascular Endothelial Growth Factors Work Xenograft Model Xenograft procedure angiogenesis base bevacizumab chemotherapy cytotoxic density design drug development drug testing effective therapy experience improved in vivo inhibitor/antagonist model development mouse model neoplastic cell novel preclinical study research study scaffold small molecule therapy resistant tumor tumor growth tumor microenvironment tumor xenograft tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The Problem: It is estimated that about 1,200 new cases of adenoid cystic carcinoma (ACC) are diagnosed each year in the United States. These tumors are characterized by relentless growth and frequent recurrence. As a consequence, the 15-year survival rate for these patients is unacceptably low (40%). Since no drug has been approved for ACC, the primary treatment still is radical surgery, which is typically associated with high morbidity and poor quality of life. The lack of cell lines and mouse models has been identified as major roadblocks for the discovery of new therapies for ACC. Improvements in the survival of patients with ACC are likely to come from studies performed in animal models that mimic the human tumor microenvironment and enable the discovery of safe and effective mechanism-based therapies for this malignancy. Hypothesis: We recently developed a method to generate human ACC cell lines that is consisted of culturing cells retrieved from surgical specimens for 7-10 days in ultra-low attachment plates. Temporary exposure to non-adherent conditions eliminates stromal cells by anoikis and purifies cultures of tumorigenic ACC. Here, we will use our new ACC cell lines to develop a method for generation of xenograft tumors with humanized vasculature that is optimized for developmental therapeutics studies. The ACC xenograft model will be used to evaluate the effect of novel small molecule inhibitors of the MDM2/Bcl-2 signaling axis in pre-clinical trials. Notably, the oncoproteins MDM2 and Bcl-2 protect tumor cells against apoptosis, correlate with the aggressiveness of ACC, and are likely involved in resistance to chemotherapy. The underlying hypothesis of this work is that therapeutic inhibition of the MDM2/Bcl-2 signaling axis sensitizes adenoid cystic carcinomas to chemotherapy in pre-clinical models of ACC. To address this hypothesis, we propose the following aims: Specific Aim #1: To develop and characterize a xenograft model of adenoid cystic carcinoma with humanized vasculature that is suitable for pre-clinical trials. Specific Aim #2: To define the effect of therapeutic inhibition of the MDM2/Bcl-2 signaling axis on adenoid cystic carcinoma growth, angiogenesis, and recurrence. Specific Aim #3: To determine the effect of therapeutic inhibition of the MDM2/Bcl-2 signaling axis on adenoid cystic carcinoma resistance to a conventional chemotherapeutic drug (Cisplatin). Significance: This proposal is centered on mechanistic studies and pre-clinical trials with novel small molecule inhibitors of the MDM2/Bcl-2 pathway using a unique xenograft model of ACC with humanized vasculature. Small molecule inhibitors of MDM2 and Bcl-2 have been well tolerated by patients in Phase I and II trials. Therefore, successful outcome of the studies proposed here can rapidly be followed by a clinical trial testing these drugs in patients with ACC. Our research team is fully committed to the development of a mechanism- based therapy that will enhance the survival and quality of life of patients with adenoid cystic carcinoma.

描述（由申请人提供）：问题：据估计，美国每年诊断出约 1,200 例新的腺样囊性癌 (ACC) 病例。这些肿瘤的特点是持续生长和频繁复发。因此，这些患者的 15 年生存率低得令人无法接受 (40%)。由于尚未批准治疗 ACC 的药物，因此主要治疗方法仍然是根治性手术，这通常与高发病率和较差的生活质量相关。细胞系和小鼠模型的缺乏已被确定为发现 ACC 新疗法的主要障碍。 ACC 患者生存率的改善可能来自于在模拟人类肿瘤微环境的动物模型中进行的研究，并能够发现针对这种恶性肿瘤的安全有效的基于机制的疗法。假设：我们最近开发了一种生成人类 ACC 细胞系的方法，该方法包括将从手术标本中取出的细胞在超低附着板中培养 7-10 天。暂时暴露于非贴壁条件可通过失巢凋亡消除基质细胞并纯化致瘤 ACC 的培养物。在这里，我们将使用我们的新 ACC 细胞系开发一种用于生成具有人源化脉管系统的异种移植肿瘤的方法，该方法针对发育治疗研究进行了优化。 ACC异种移植模型将用于评估MDM2/Bcl-2信号轴的新型小分子抑制剂在临床前试验中的效果。值得注意的是，癌蛋白 MDM2 和 Bcl-2 可以保护肿瘤细胞免于凋亡，与 ACC 的侵袭性相关，并且可能与化疗耐药有关。这项工作的基本假设是，在 ACC 临床前模型中，治疗性抑制 MDM2/Bcl-2 信号轴会使腺样囊性癌对化疗敏感。为了解决这一假设，我们提出以下目标：具体目标#1：开发并表征具有适合临床前试验的人源化脉管系统的腺样囊性癌异种移植模型。具体目标#2：确定治疗性抑制 MDM2/Bcl-2 信号轴对腺样囊性癌生长、血管生成和复发的影响。具体目标#3：确定 MDM2/Bcl-2 信号轴的治疗性抑制对腺样囊性癌对传统化疗药物（顺铂）的耐药性的影响。意义：该提案的重点是新型小分子抑制剂的机制研究和临床前试验。 MDM2/Bcl-2 通路使用具有人源化脉管系统的独特 ACC 异种移植模型。 MDM2 和 Bcl-2 的小分子抑制剂在 I 期和 II 期试验中已被患者良好耐受。因此，本文提出的研究取得成功后，可以很快在 ACC 患者中进行临床试验来测试这些药物。我们的研究团队完全致力于开发一种基于机制的疗法，以提高腺样囊性癌患者的生存率和生活质量。