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

• 批准号: 8890729
• 负责人: Fengzhi Li
• 金额: $ 18.47万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890729
• 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; Health; Human; In Vitro; Incidence; Induction of Apoptosis; Inhibition of Apoptosis; Intravenous; Investments; Lead; Legal patent; Libraries; Licensing; MCL1 gene; 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; radiation resistance; research clinical testing; response; small molecule; subcutaneous; survivin; therapy development; tumor xenograft

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袭性的人类癌症，其生存率非常低（5年生存率为3-6%）并且没有任何改善在结果中。例如，在美国，估计的胰腺癌新病例和该疾病的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）具有惊人的固有抵抗力。该 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功效，该药物旨在克服因一种或多种抗凋亡蛋白表达增加而导致的治疗抵抗的常见机制（生存素、Mcl-1、XIAP、cIAP2）来自细胞凋亡抑制剂 (IAP) 和 Bcl-2 家族。胰腺癌治疗抵抗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，FL118 以独立于 p53 状态（野生型、突变型或无效）的方式选择性抑制生存素、XIAP、cIAP2 和 Mcl-1 的表达。我们一致报道，许多非胰腺癌对 FL118 敏感，与其 p53 状态无关。我们假设，虽然 FL118 与喜树碱具有结构相似性，但 FL118 是一种新型抗癌药物，其作用机制不同于拓扑替康等其他喜树碱类似物，并且与目前 FDA 批准的喜树碱类似物（例如托泊替康）相比，FL118 更适合治疗胰腺癌。 ）或其他抗癌剂（吉西他滨）。该假设将在三个具体目标中进行检验： 目标 1：使用拓扑替康作为比较对照来表征 FL118 靶点选择性。我们将使用多种方法来确定 FL118 目标选择性。这包括针对 Top1 突变的治疗耐药因素的 FL118 和拓扑替康；存活蛋白、Mcl-1、XIAP和/或cIAP2的表达； p53突变体或p53无效； ABCG2/BCRP或ABCC4/MRP4的表达；和诱导细胞凋亡。目标 2：确定 FL118 在抗性人胰腺癌细胞异种移植小鼠模型中的功效。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。目标 3：确定 FL118 对直接源自胰腺癌患者的异种移植物的功效。托泊替康和吉西他滨也将用作该系统功效研究的比较对照。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。我们期望这个项目不仅能为胰腺癌的有效治疗提供新的希望和前景，而且还可能为征服这种致命疾病开辟新的研究策略或方向。

项目成果

Development and validation of a compact on-person storage device (SMHeartCard) for emergency access to acetylsalicylic acid and nitroglycerin.

开发和验证紧凑型个人存储设备（SMHeartCard），用于紧急获取乙酰水杨酸和硝酸甘油。

• 发表时间: 2020-01
• 作者: Le, Tyson;Paterson, D Ian;Davies, Neal M;Mackey, John R
• 通讯作者: Mackey, John R

FL118, a novel camptothecin analogue, overcomes irinotecan and topotecan resistance in human tumor xenograft models.

FL118 是一种新型喜树碱类似物，可克服人类肿瘤异种移植模型中的伊立替康和拓扑替康耐药性。

• 发表时间: 2015-10-15
• 期刊: American journal of translational research
• 作者: X. Ling;Xiaojun Liu;Kai Zhong;N. Smith;J. Prey;Fengzhi Li
• 通讯作者: Fengzhi Li

New trends for overcoming ABCG2/BCRP-mediated resistance to cancer therapies.

克服 ABCG2/BCRP 介导的癌症治疗耐药性的新趋势。

• 发表时间: 2015-12-30
• 作者: Westover, David;Li, Fengzhi
• 通讯作者: Li, Fengzhi

Antitumor activity of FL118, a survivin, Mcl-1, XIAP, and cIAP2 selective inhibitor, is highly dependent on its primary structure and steric configuration.

FL118 是一种生存素、Mcl-1、XIAP 和 cIAP2 选择性抑制剂，其抗肿瘤活性高度依赖于其一级结构和空间构型。

• DOI: 10.1021/mp4004282
• 发表时间: 2014-01-06
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Jiuyang Zhao;X. Ling;Shousong Cao;Xiaojun Liu;S. Wan;Tao Jiang;Fengzhi Li
• 通讯作者: Fengzhi Li

FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance.

FL118 是一种新型喜树碱衍生物，对 ABCG2 表达不敏感，并且在具有 ABCG2 诱导耐药性的结肠癌和肺癌模型中与伊立替康相比显示出更高的疗效。

• 发表时间: 2015-04-28
• 影响因子: 37.3
• 作者: Westover, David;Ling, Xiang;Lam, Hong;Welch, Jacob;Jin, Chunyang;Gongora, Celine;Del Rio, Maguy;Wani, Mansukh;Li, Fengzhi
• 通讯作者: Li, Fengzhi