Targeting Telomerase in Pancreateic Cancer

靶向胰腺癌中的端粒酶

基本信息

批准号：
8688966
负责人：
ANTHONY J BERDIS
金额：
$ 16.33万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8688966
关键词：
Adult Affinity Aging-Related Process Apoptosis Apoptotic Binding Binding Sites Cancer Biology Cancer Cell Growth Cancer cell line Capsid Proteins Cell Death Cell Death Signaling Process Cell division Cells Characteristics DNA DNA Damage DNA Sequence Enzymes Event Genomic Instability Human Human Chromosomes Knowledge Left Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Measures Methods Neoplasm Metastasis Nucleosides Nucleotides Pancreas Pancreatic carcinoma Phase II Clinical Trials Play Poison Process Proteins Ribonucleoproteins Right-On Role Scheme Side Single-Stranded DNA Specificity Telomerase Telomerase Inhibitor Telomerase inhibition Telomere Capping Telomere Shortening Telomere-Binding Proteins Testing Therapeutic Time Tissues Tumor Suppressor Proteins Up-Regulation base cancer cell cancer stem cell carcinogenesis cell killing design innovation neoplastic cell new therapeutic target normal aging novel nucleotide analog pancreatic cancer cells pancreatic cell line pancreatic neoplasm public health relevance response telomere trait treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Telomeres cap and protect the ends of all human chromosomes. In healthy adult tissue, telomeres shorten with each round of cell division as part of the normal aging process. This mechanism limits human cells to a finite number of cell divisions before induction of programmed cell death and therefore serves as a tumor suppressor. In cancer cells, however, an enzyme called telomerase is upregulated to nullify the limited number of cell divisions. As such, cancer cells are capable of infinite division, which allows proliferation of ~90% of all pancreatic cancers. Due to this unique and critical role in cancer biology, telomerase provides a novel target for innovative therapeutics. The purpose of the present proposal is to explore a completely new mechanism toward using telomerase as an anti-cancer target. In our approach, we will design non-native nucleotide analogs to be preferentially and selectively incorporated by telomerase into telomere DNA. Once incorporated, the non-native nucleotides should abrogate binding of essential telomere-end binding proteins such as the Protection of Telomeres 1 (POT1), which is highly specific for telomere DNA sequence. Abrogation of POT1 binding induces cell death through a cascade of DNA damage events. The cell- killing potential of these non-native nucleotide compounds will be validated by measuring their potency and selectivity against telomerase-positive, pancreatic cancer cell lines. We predict that our strategy will provide a selective mechanism to potentially treat human pancreatic cancer.

描述（由申请人提供）：端粒帽和保护所有人类染色体的末端。在健康的成年组织中，作为正常衰老过程的一部分，每一轮细胞分裂都会缩短端粒。该机制将人类细胞限制为诱导程序性细胞死亡之前的细胞分裂数量有限，因此作为肿瘤抑制剂。然而，在癌细胞中，一种称为端粒酶的酶被上调以使细胞分裂数量有限。因此，癌细胞能够无限分裂，这允许所有胰腺癌的约90％。由于这种在癌症生物学中的独特而关键的作用，端粒酶为创新治疗剂提供了新的目标。本提案的目的是探索一种全新的机制，用于使用端粒酶作为抗癌目标。在我们的方法中，我们将设计非本地核苷酸类似物，以优先和选择性地通过端粒酶合并到端粒DNA中。一旦合并，非本地核苷酸应消除必需端粒结合蛋白的结合，例如对端粒1（POT1）的保护，这对于端粒DNA序列高度特异。废除POT1结合通过一系列DNA损伤事件诱导细胞死亡。这些非本地核苷酸化合物的细胞杀伤潜力将通过测量其对端粒酶阳性胰腺癌细胞系的效力和选择性来验证。我们预测，我们的策略将提供一种选择性治疗人胰腺癌的选择性机制。