HDAC6-Selective Inhibitors for Pancreatic Cancer Treatment

描述（由申请人提供）：胰腺癌是美国癌症死亡的第五大原因。尽管在了解其分子生物学方面做出了巨大的努力，但常规治疗收效甚微。由于这种疾病的高度转移性，只有15- 20%的患者可以接受手术治疗。因此，迫切需要开发和表征可以单独使用或与传统疗法一起使用的新治疗剂。HDAC有4类，据推测，癌细胞中HDAC活性的增加可能导致肿瘤抑制基因如p16、p21和gelsolin的表观遗传沉默。事实上，用广谱i /II类HDAC抑制剂（HDACI） SAHA治疗胰腺癌细胞可导致p21上调、生长抑制和诱导凋亡。UIC的Kozikowski教授团队最近产生了新型HDACIs，其中一些在体外对HDAC6和HDAC3表现出低pM活性。用这些化合物治疗胰腺癌细胞可导致G1和/或G2阻滞并诱导凋亡。此外，数据表明，这些新型hdac中的一些会导致DNA损伤检查点激酶Chk1的丢失。据推测，它们可以使胰腺肿瘤细胞对基因毒性药物敏感。我们相信，这些hdac与DNA损伤诱导药物（如吉西他滨）联合使用，将比单独使用吉西他滨的常规治疗提供显著的治疗效果。为了验证这一假设，我们提出(1)重新合成在UIC中产生的12个最活跃的hdac，并合成10个新的类似物并测试它们的同工异构体选择性；(2)明确HDACIs对胰腺肿瘤细胞增殖和体外存活的生物学效应；(3)确定5种最佳hdac在吉西他滨联合给药的情况下对已建立的胰腺肿瘤细胞系异种移植物的体内疗效。这些研究将提供关于hdac与引起DNA损伤的治疗药物联合使用的重要信息，以及与这些化合物治疗胰腺癌的安全性和有效性相关的有价值的结构-活性关系（SAR）数据，同时允许衡量寻找“安全”治疗所需的同种异构体选择性的程度。本文提出的hdac的生物学特性也可能允许更好地将特定亚型与致瘤事件联系起来。在I期提案中确定的两到三种最佳hdac将成为II期申请的主题，以资助ADMET工作，旨在将其中一种化合物推进临床研究。公共卫生相关性：胰腺癌是美国癌症死亡的第五大原因，常规化疗治疗效果差，而由于该疾病的高度转移性，只有15-20%的患者可以进行手术治疗。本申请旨在研究一系列新的组蛋白去乙酰化酶（hdac）抑制剂的能力，这些抑制剂已被证明在体外抑制胰腺癌细胞的生长并导致细胞凋亡，与常规化疗药物吉西他滨联合抑制小鼠胰腺肿瘤细胞系异种移植的生长。积极的结果将导致第二阶段申请，以资助ADMET工作，旨在将这些化合物之一推进临床研究。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fifth leading cause of cancer death in the US. Despite tremendous efforts aimed at understanding its molecular biology, conventional treatment has had little impact. Due to the highly metastatic nature of the disease, surgery is available to only 15- 20% of patients. Thus, the development and characterization of new therapeutic agents that can be used alone or together with conventional therapies is desperately needed. There are 4 classes of HDACs, and it is hypothesized that increased HDAC activity in cancer cells may contribute to the epigenetic silencing of tumor suppressor genes such as p16, p21 and gelsolin. In fact, treatment of pancreatic cancer cells with the broad spectrum classI/II HDAC inhibitor (HDACI), SAHA, leads to upregulation of p21, growth inhibition and induction of apoptosis. The team of Professor Kozikowski at UIC has recently generated novel classes of HDACIs, several of which show low pM activity toward HDAC6 and HDAC3 in vitro. Treatment of pancreatic cancer cells with these compounds results in a G1 and/or G2 arrest and induction of apoptosis. In addition, the data indicate that some of these novel HDACIs cause loss of the DNA damage checkpoint kinase, Chk1. It is hypothesized that they can sensitize pancreatic tumor cells to genotoxic agents. We believe that a combination of these HDACIs with DNA damage-inducing agents, such as gemcitabine, will provide significant therapeutic benefit compared to the conventional treatment, gemcitabine alone. To test this hypothesis, we propose to (1) re-synthesize the 12 most active HDACIs made at UIC, and to synthesize 10 new analogs and test them for isoform selectivity; (2) to define biological effects of HDACIs on pancreatic tumor cell proliferation and survival in vitro; and (3) to determine the in vivo efficacy of the 5 best HDACIs on established pancreatic tumor cell line xenografts with co-administration of gemcitabine. These studies will provide important information regarding the use of HDACIs in combination with therapeutic agents that cause DNA damage, and valuable structure-activity relationship (SAR) data relevant to the safety and efficacy of these compounds in the treatment of pancreatic cancer, while allowing to gauge the extent to which isoform selectivity is required in finding a "safe" therapy. The biological characterization of the HDACIs presented herein may also allow to better link specific isoforms to tumorigenic events. The two or three best HDACIs identified in this Phase I proposal will be the subject of a Phase II application to fund ADMET work aimed at advancing one of these compounds into clinical studies. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fifth leading cause of cancer death in the US and is poorly treatable by conventional chemotherapy, while surgery is available to only 15-20% of patients due to the highly metastatic nature of the disease. The present application aims at investigating the ability of a novel series of inhibitors of histone deacetylases (HDACs), which have been shown to inhibit pancreatic cancer cell growth in vitro and lead to apoptosis, to inhibit the growth of pancreatic tumor cell line xenografts in mice in combination with the conventional chemotherapeutic agent, gemcitabine. Positive results would lead to a Phase II application to fund ADMET work aimed at advancing one of these compounds into clinical studies.