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，在美国每年大约有1200例新的腺样囊性癌（ACC）被诊断出来。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%）。由于没有药物被批准用于治疗ACC，主要治疗方法仍然是根治性手术，这通常与高发病率和低生活质量有关。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患者生存期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这种恶性肿瘤治疗方法。假设：我们最近开发了一种产生人类ACC细胞系的方法，该方法由从手术标本中提取的培养细胞在超低附着板中培养7-10天组成。暂时暴露在非贴壁条件下，通过anoikis消除基质细胞，并纯化致瘤性ACC的培养物。在这里，我们将使用我们新的ACC细胞系来开发一种具有人源化血管系统的异种移植肿瘤的生成方法，该方法对发育治疗研究进行了优化。ACC异种移植模型将用于在临床前试验中评估新型MDM2/Bcl-2信号轴小分子抑制剂的效果。值得注意的是，癌蛋白MDM2和Bcl-2保护肿瘤细胞免受凋亡，与ACC的侵袭性相关，并可能参与对化疗的抵抗。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：开发和表征具有人源化血管的腺样囊性癌异种移植模型，该模型适用于临床前试验。特异性目的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。特异性目的#3：确定治疗性抑制MDM2/Bcl-2信号轴对腺样囊性癌对常规化疗药物（顺铂）耐药的影响。意义：本提案主要集中在机制研究和新的小分子抑制剂的临床前试验

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.