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

描述（由申请人提供）：在过去十年中，虽然总体癌症发病率趋于下降，但胰腺癌仍然是最具侵袭性的人类癌症，生存率非常低（5年生存率为3-6%），结局无改善。例如，在美国，胰腺癌的估计新病例和死亡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）的惊人的固有抗性。该R21探索性项目的目标是探索一种新型抗癌药（命名为FL 118）的机制新奇和抗胰腺癌疗效，该抗癌药旨在克服由凋亡抑制剂（IAP）和Bcl-2家族的一种或多种抗凋亡蛋白（生存素、Mcl-1、XIAP、cIAP 2）表达增加引起的治疗抗性的常见机制。胰腺癌治疗抗性的另一个主要机制是功能性p53的丧失（突变或无效）。在这方面，FL 118以不依赖于p53状态（野生型、突变型或无效）的方式选择性地抑制存活素、XIAP、cIAP 2和Mcl-1的表达。因此，我们已经报道了许多非胰腺癌对FL 118敏感，与其p53状态无关。我们假设，尽管FL 118与喜树碱具有结构相似性，但FL 118是一种新型抗癌药，其作用机制与其他喜树碱类似物（如托泊替康）不同，并且与目前FDA批准的喜树碱类似物（如托泊替康）或其他抗癌药（吉西他滨）相比，FL 118在治疗胰腺癌方面具有上级优势。将在三个特定目的中检验该假设：目的1：使用托泊替康作为比较对照，表征FL 118靶标选择性。我们将使用多种方法来确定FL 118的目标选择性。这包括FL 118和拓扑替康对Top1突变的治疗抗性因素的响应;生存素、Mcl-1、XIAP和/或cIAP 2的表达; p53突变体或p53无效; ABCG 2/BCRP或ABCC 4/MRP 4的表达;以及细胞凋亡的诱导。目的2：确定FL 118在治疗抗性人胰腺癌细胞建立的异种移植物的小鼠模型中的功效。我们将使用拓扑替康和吉西他滨（临床实践中最常用的胰腺癌治疗单一方案药物）进行疗效比较研究。目的3：确定FL 118对直接来源于胰腺癌患者的异种移植物的功效。拓扑替康和吉西他滨也将用作该系统中疗效研究的比较对照。与上述目标2相同，这些研究将使用皮下和原位异种移植肿瘤模型。我们期望该项目不仅为胰腺癌的有效管理提供新的希望和前景，而且还可能开辟新的研究策略或方向，以征服这种致命的疾病。

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.