Targeting Telomerase in Pancreateic Cancer

靶向胰腺癌中的端粒酶

基本信息

批准号：
8583535
负责人：
ANTHONY J BERDIS
金额：
$ 21.74万
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/8583535
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 Line 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 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）：端粒覆盖并保护所有人类染色体的末端。在健康的成人组织中，端粒随着每轮细胞分裂而缩短，这是正常衰老过程的一部分。这种机制在诱导程序性细胞死亡之前将人类细胞限制在有限数量的细胞分裂中，因此可以作为肿瘤抑制因子。然而，在癌细胞中，一种称为端粒酶的酶被上调，以消除有限数量的细胞分裂。因此，癌细胞能够无限分裂，这使得约 90% 的胰腺癌能够增殖。由于端粒酶在癌症生物学中的独特而关键的作用，为创新疗法提供了新的靶点。本提案的目的是探索一种利用端粒酶作为抗癌靶点的全新机制。在我们的方法中，我们将设计非天然核苷酸类似物，使其优先且选择性地被端粒酶掺入端粒 DNA 中。一旦掺入，非天然核苷酸就会消除必需的端粒末端结合蛋白的结合，例如端粒保护 1 (POT1)，它对端粒 DNA 序列具有高度特异性。 POT1 结合的取消会通过一系列 DNA 损伤事件诱导细胞死亡。这些非天然核苷酸化合物的细胞杀伤潜力将通过测量它们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潜在治疗人类胰腺癌的选择性机制。