HDAC3 - a therapeutic target in PDA

描述（由申请人提供）：胰腺导管腺癌，PDA，每年约有30,000名美国人被诊断出来。总体5年生存率不到5%，每年约有3.3万美国人死于肺癌，成为癌症死亡的第四大原因。这使得PDA成为最致命的恶性肿瘤之一。最近在大量PDA中发现了Ski蛋白的表达增加（约70%）。这种增加的表达与不良预后相关，然而Ski表达导致不良预后的机制尚不清楚。最近，我们发现Ski的表达增加导致I类组蛋白去乙酰化酶HDAC3的表达增加。在几种人类癌症中已发现1类hdac水平升高，并与不良预后相关，因此HDAC3水平升高很可能与Ski阳性PDA的不良预后有关。HDAC抑制剂在临床上用于治疗这些酶。然而，抑制hdac存在一些缺陷，因为这些酶在细胞发育和稳态中起关键作用，并且在最近的临床试验中注意到有害的副作用。因此，在本提案中，我们将采取不同的方法，合成将被class1 HDAC活性激活的药物。我们假设PDA中HDAC3水平的升高将为这类新的前药提供治疗靶点。在本提案中，我们将通过设计一个

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma, PDA, is diagnosed in approximately 30,000 Americans every year. With an overall 5-year survival rate of less than 5% it kills approximately 33,000 Americans a year, making it the fourth leading cause of cancer death. This makes PDA one of the deadliest of all malignancies. Recently increased expression of the Ski protein has been found in a large number of PDA's (approx 70%). This increased expression was associated with a bad prognosis, however the mechanism by which Ski expression leads to a bad prognosis is unclear. Recently we determined that increased expression of Ski results in increased expression of the class I histone deacetylase HDAC3. Increased levels of class 1 HDACs have been found in several human cancers and are associated with bad prognosis and thus the increased level of HDAC3 may well contribute to the bad prognosis of Ski- positive PDA. HDAC inhibitors are in use in the clinic to therapeutically target these enzymes. However there are several drawbacks associated with inhibition of HDACs, since these enzymes play key roles in cell development and homeostasis, and deleterious side effects have been noted in recent clinical trials. Therefore in this proposal we will take a different approach and synthesize drugs that will be activated by class1 HDAC activity. We hypothesize that the increased HDAC3 levels in PDA will provide a therapeutic target for this new class of prodrugs. In this proposal we will test this hypothesis by designing a new class of pro-drugs that are co-activated by HDAC3 activity together with the well- characterized tumor-associated protease activity associated with PDA and determine the effect of these drugs on PDA cell lines in vitro as well as in vivo. These studies will identify HDAC3 as a defined molecular target for future clinical intervention. Our new class of prodrugs that target the increased levels of class 1 HDACs associated with human cancers, including PDA, and due to its two-step activation process will hopefully be more specific for tumor cells and have lower non-specific toxicity and have the potential to provide some help in treating this dreadful disease.