An inhibitor of multiple anti-apoptotic gene products for pancreatic cancer

描述(申请人提供)：在过去的十年中，虽然总体癌症发病率呈下降趋势，但胰腺癌仍然是最具侵袭性的人类癌症，存活率非常低(5年存活率为3-6%)，预后没有改善。例如，在美国，估计的胰腺癌新病例和死于这一疾病的人数在过去六年中有所增加(2008年：37 680例新病例和34 290例死亡；2013年：45 220例新病例和38 460例死亡)。这种疾病的挑战基本上是由于胰腺癌对治疗(化疗、放疗)具有惊人的内在抵抗力。这个R21探索性项目的目标是探索一种新型抗癌药物(命名为FL118)的机制新颖性和抗胰腺癌疗效，该药物旨在克服因一种或多种抗凋亡蛋白(Survivin、Mcl-1、XIAP、cIAP2)的表达增加而导致的治疗耐药机制。胰腺癌治疗耐药的另一个主要机制是功能性P53的丢失(突变或缺失)。在这一点上，FL118选择性地抑制Survivin、XIAP、cIAP2和Mcl-1的表达，这是一种P53状态(野生型、突变型或空)不依赖的方式。我们一直报道，许多非胰腺癌对FL118敏感，与它们的P53状态无关。我们推测，虽然FL118在结构上与喜树碱相似，但它是一种新型抗癌药物，其作用机制有别于其他喜树碱类似物，如拓扑替康，与FDA批准的喜树碱类似物(如拓扑替康)或其他抗癌药物(吉西他滨)相比，FL118在治疗胰腺癌方面更具优势。这一假设将在三个具体目标中进行检验：目标1：使用Topotecan作为比较对照来表征FL118靶标的选择性。我们将使用多种方法来确定FL118靶标的选择性。这包括Fl118和Topotecan对Top1突变耐药因子的反应；Survivin、Mcl-1、XIAP和/或cIAP2的表达；p53突变或p53缺失；ABCG2/BCRP或ABCC4/MRP4的表达；以及诱导细胞凋亡。目的：在耐药人胰腺癌细胞建立的小鼠移植瘤模型中检测Fl118的疗效。我们将同时使用拓扑替康和吉西他滨(临床上治疗胰腺癌最常用的单一方案药物)进行疗效比较研究。目的：检测FL118对胰腺癌患者直接来源的异种移植瘤的疗效。拓扑替康和吉西他滨也将被用作该系统疗效研究的对照。与上面的目标2相同，皮下和原位异种移植肿瘤模型将在这些研究中使用。我们期待这个项目不仅为胰腺癌的有效治疗提供新的希望和前景，而且可能为征服这种致命的疾病开辟新的研究策略或方向。

DESCRIPTION (provided by applicant): In the past decade, while the overall cancer incidence rate tends to declining, pancreatic cancer remains the most aggressive human cancer with a very poor survival rate (3-6% for 5-year survival) and no improvement in outcomes. For example, in the United States, the estimated new cases of pancreatic cancer and deaths from this disease have grown over the past six years (2008: 37,680 new cases and 34,290 deaths; 2013: 45,220 new cases and 38,460 deaths). The challenge of this disease is basically due to the striking inherent resistance of pancreatic cancer to treatment (chemotherapy, radiation). The goal of this R21 exploratory project is to explore the mechanistic novelty and anti-pancreatic cancer efficacy of a novel anticancer agent (designated FL118) that is designed to overcome a common mechanism of treatment resistance resulting from the increased expression of one or more antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) from the inhibitor of apoptosis (IAP) and Bcl-2 families. The other major mechanism of treatment resistance of pancreatic cancer is the loss of functional p53 (mutated or null). In this regard, FL118 selectively inhibits the expression of survivin, XIAP, cIAP2 and Mcl-1 in a p53 status (wild type, mutant or null) independent manner. Consistently, we have reported that many non-pancreatic cancers are sensitive to FL118, independently of their p53 status. We hypothesize that although FL118 has structural similarity to camptothecin, FL118 is a novel anticancer agent with mechanisms of action distinct from other camptothecin analogs such as topotecan, and FL118 is superior for treatment of pancreatic cancer when compared to current FDA approved camptothecin analogs (e.g. topotecan) or other anticancer agents (gemcitabine). The hypothesis will be tested in three Specific Aims: Aim 1: Characterize FL118 target selectivity using topotecan as a comparative control. We will use multiple approaches to determine FL118 target selectivity. This includes FL118 and topotecan in response to treatment resistant factors of Top1 mutations; expression of survivin, Mcl-1, XIAP and/or cIAP2; p53 mutant or p53 null; expression of ABCG2/BCRP or ABCC4/MRP4; and induction of apoptosis. Aim 2: Determine FL118 efficacy in mouse models of treatment resistant human pancreatic cancer cell-established xenografts. We will use both topotecan and gemcitabine (the most commonly used single regimen drug for pancreatic cancer treatment in clinical practice) for efficacy comparative studies. Aim 3: Determine FL118 efficacy against xenografts directly derived from pancreatic cancer patients. Both topotecan and gemcitabine will also be used as comparative controls for efficacy studies in this system. Same as in Aim 2 above, both subcutaneous and orthotopic xenograft tumor models will be used in these studies. We expect that this project would not only provide new hopes and perspectives for effective management of pancreatic cancer, but may also open new research strategies or directions to conquer this deadly disease.