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

多种胰腺癌抗凋亡基因产物的抑制剂

基本信息

批准号：
8694557
负责人：
Fengzhi Li
金额：
$ 22.16万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-10 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8694557
关键词：
ABCG2 gene Antineoplastic Agents Apoptosis Inhibitor Apoptotic BCL2 gene BIRC4 gene Biological Assay CDKN1A gene Camptothecin Camptothecin Analogue Cancer Patient Cessation of life Clinic Clinical Trials Comparative Study Development Disease Dose Drug Formulations Drug Targeting Drug resistance Employee Strikes FDA approved Family Family member Funding Genes Goals Human In Vitro Incidence Induction of Apoptosis Inhibition of Apoptosis Intravenous Investments Lead Legal patent Libraries Licensing MCL1 protein Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modeling Mutate Mutation Names Outcome Pharmaceutical Preparations Pilot Projects Play Protein Family Proteins Radiation Regimen Reporting Research Resistance Resistance development Role Specificity Survival Rate System Testing Therapeutic Index Topotecan Toxic effect United States United States National Institutes of Health Xenograft procedure analog cancer cell cancer therapy cancer type cell growth chemotherapy clinical application clinical practice comparative design functional loss gemcitabine high throughput screening improved in vivo inhibitor/antagonist irinotecan mouse model mutant novel pancreatic cancer cells public health relevance radiation resistance research clinical testing response small molecule subcutaneous survivin therapy development tumor xenograft

项目摘要

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.

描述（由申请人提供）：在过去的十年中，虽然总体癌症发病率趋于下降，但胰腺癌仍然是最具侵略性的人类癌症，生存率较差（5年生存率为3-6％），结果没有改善。例如，在美国，估计的胰腺癌和这种疾病死亡的新病例在过去六年中增长（2008：37,680：37,680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的固有抗药性（化学疗法，放射线）。 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.胰腺癌治疗耐药性的另一个主要机制是功能性p53（突变或无效）的丧失。在这方面，FL118在p53状态（野生型，突变体或无效的方式）中有选择地抑制Survivin，XIAP，CIAP2和MCL-1的表达。一致地，我们报告说，许多非胰腺癌对FL118的敏感，与其p53状态无关。我们假设，尽管FL118与Camptothecin具有结构相似性，但FL118是一种新型的抗癌剂，其作用机制与其他camptothecin类似物（如拓扑托克）不同，而FL118则在与当前经过FDA批准的Camptothecin Analogs Antients（例如其他替代品）相比（例如其他替代品）（例如其他甲壳虫）（例如其他tumcincine）（例如，Gembine）（例如，FL118）在治疗胰腺癌方面均优异。该假设将以三个特定的目的进行检验：目标1：以拓扑替康为比较对照来表征FL118目标选择性。我们将使用多种方法来确定FL118目标选择性。这包括响应TOP1突变的抗治疗因子的FL118和拓扑甘丹； Survivin，Mcl-1，XIAP和/或CIAP2的表达； p53突变体或p53 null; ABCG2/BCRP或ABCC4/MRP4的表达；和凋亡的诱导。 AIM 2：确定耐药性人胰腺癌细胞建立的异种移植的小鼠模型中的FL118功效。我们将同时将拓扑替康和吉西他滨（在临床实践中用于胰腺癌治疗的最常用的单一治疗药物）进行疗效比较研究。 AIM 3：确定直接来自胰腺癌患者的异种移植物的FL118疗效。拓平和吉西他滨都将用作该系统功效研究的比较对照。与上面的AIM 2相同，这些研究将使用皮下和原位异种移植肿瘤模型。我们预计，该项目不仅可以为有效管理胰腺癌提供新的希望和观点，而且还可以开放新的研究策略或征服这种致命疾病的方向。