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

描述（由申请人提供）：问题：据估计，在美国每年诊断出约1,200例腺样囊性癌（ACC）新病例。这些肿瘤的特点是无情的增长和频繁复发。因此，这些患者的15年生存率低得令人无法接受（40%）。由于没有药物被批准用于ACC，主要治疗仍然是根治性手术，这通常与高发病率和低生活质量相关。缺乏细胞系和小鼠模型已被确定为发现ACC新疗法的主要障碍。ACC患者生存率的改善可能来自模拟人类肿瘤微环境的动物模型研究，并能够发现安全有效的基于机制的治疗方法。假设：我们最近开发了一种产生人ACC细胞系的方法，该方法包括在超低附着板中培养从手术标本中取出的细胞7-10天。暂时暴露于非粘附条件下通过失巢凋亡消除基质细胞，并纯化致瘤性ACC. Here的培养物，我们将使用我们的新ACC细胞系开发一种方法，用于生成具有人源化血管系统的异种移植肿瘤，该方法针对发育治疗学研究进行了优化。ACC异种移植模型将用于在临床前试验中评价MDM 2/Bcl-2信号传导轴的新型小分子抑制剂的作用。值得注意的是，癌蛋白MDM 2和Bcl-2保护肿瘤细胞免于凋亡，与ACC的侵袭性相关，并且可能参与对化疗的抵抗。这项工作的基本假设是，治疗性抑制MDM 2/Bcl-2信号传导轴敏感的腺样囊性癌化疗ACC. To解决这一假设的临床前模型，我们提出了以下目标：具体目标#1：开发和表征腺样囊性癌的异种移植模型与人源化的血管系统，是适合于临床前试验。具体目标#2：明确治疗性抑制MDM 2/Bcl-2信号传导轴对腺样囊性癌生长、血管生成和复发的影响。具体目标#3：确定治疗性抑制MDM 2/Bcl-2信号传导轴对腺样囊性癌对常规化疗药物（顺铂）耐药性的影响。意义：该提案的重点是新的小分子抑制剂的机制研究和临床前试验。 使用具有人源化脉管系统的ACC的独特异种移植物模型的MDM 2/Bcl-2途径。在I期和II期试验中，MDM 2和Bcl-2的小分子抑制剂已被患者良好耐受。因此，成功的结果，在这里提出的研究可以迅速随后的临床试验测试这些药物在ACC. Our研究团队的患者是完全致力于开发一种机制为基础的治疗，将提高生存和生活质量的患者腺样囊性癌。 公共卫生相关性：由于缺乏合适的实验动物模型，腺样囊性癌安全有效的治疗方法一直受到阻碍。该提案的重点是开发和表征一种新的腺样囊性癌小鼠模型，并评估靶向这些肿瘤中致癌蛋白MDM 2和Bcl-2的新药。我们的最终目标是开发一种基于机制的治疗方法，提高腺样囊性癌患者的生存率和生活质量。 carcinoma.

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. PUBLIC HEALTH RELEVANCE: The development of safe and effective therapies for adenoid cystic carcinoma has been hindered by the lack of appropriate experimental animal models. This proposal is focused on the development and characterization a new mouse model of adenoid cystic carcinoma, and on the evaluation of novel drugs that target the oncogenic proteins MDM2 and Bcl-2 in these tumors. Our ultimate goal is to develop a mechanism-based therapy that prolongs the survival and enhances the quality of life of patients with adenoid cystic carcinoma.