Targeting Shared Vulnerabilities in Alternate Telomere Lengthening (ALT) Cancers

针对替代端粒延长 (ALT) 癌症的共同弱点

基本信息

批准号：
10390601
负责人：
CHARLES Patrick REYNOLDS
金额：
$ 38.41万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10390601
关键词：
ATM activation ATRX gene Adult Biological Assay Biological Markers Cancer Biology Cancer Histology Cancer Model Cancer Patient Cancer cell line Cell Line Cells Chemicals Childhood Chromosomes Chronic Clinical Clinical Trials Code Colon Carcinoma DAXX gene DNA DNA Damage DNA Repair Data Dependence Detection Development Dominant-Negative Mutation Enrollment Functional disorder Future Genetic Recombination Histology Human Investigational Drugs Laboratories Malignant Childhood Neoplasm Malignant Neoplasms Modeling Molecular Mutation Neuroblastoma Nucleoproteins Outcome Patients Phenotype Phosphorylation Phosphotransferases Pre-Clinical Model Prevalence Prognosis Resistance Rhabdomyosarcoma Ribonucleoproteins Signal Transduction Soft tissue sarcoma Surveys TERF1 gene TP53 gene Telomerase Telomere Maintenance Testing Therapeutic Effect Tumor Markers Validation Xenograft Model Xenograft procedure ataxia telangiectasia mutated protein base cancer cell cancer type chemotherapy cytotoxic drug standard effective therapy exome sequencing genome sequencing genomic profiles inhibitor irinotecan kinase inhibitor knock-down mutant new therapeutic target novel novel therapeutics osteosarcoma overexpression patient derived xenograft model protein activation refractory cancer resistance mechanism response small hairpin RNA small molecule telomere temozolomide transcriptome transcriptome sequencing triple-negative invasive breast carcinoma tumor whole genome

项目摘要

Abstract Telomeres are nucleoproteins with TTAGGG DNA repeats at the ends of chromosomes that protect coding DNA from erosion and detection as DNA damage. Telomere maintenance is necessary for cancer cells to have unlimited proliferation capacity. Most cancers maintain their telomeres via activation of the ribonucleoprotein telomerase. Cancers with low or no telomerase activity often use another mechanism to extend their telomeres, the Alternative Lengthening of Telomeres (ALT) in which telomeres are maintained via homologous telomeric-DNA recombination, but the mechanism is still poorly understood. ALT+ tumors contain extra-chromosomal telomeric DNA C-circles, which (detected with a unique PCR assay) provides a specific and sensitive ALT biomarker. Employing the C-circle assay we have surveyed a variety of childhood and adult cancers and found 11 cancer histologies with ALT-positivity ranging from 10% to 74% and an additional 5 cancer histologies with 1 to 5% that are ALT+. ALT cancers have a poor clinical outcome and regardless of histology ALT+ cancer cell lines manifest high resistance to DNA damaging agents relative to telomerase+ cancers. ALT cancers have dysfunctional telomeres, which provides unique vulnerabilities that can serve as novel therapeutic targets. We have recently demonstrated high ATM kinase activation in ALT neuroblastoma leads to resistance to DNA damaging chemotherapy that can be reversed with a clinical-stage ATM inhibitor AZD0156. Based on our data we hypothesize that ALT+ cancers share both common mechanisms of resistance to standard therapies and common vulnerabilities that may be exploited for therapy. To enhance studies of ALT+ cancer biology, discovery and validation of novel therapeutic targets, and to enable comparing ALT+ cancers across a range of histologies we have assembled a large panel of ALT+ patient-derived cell lines (PDCLs) and patient-derived xenografts (PDXs) and comparator telomerase+ PDCLs and PDXs, including pediatric cancers (neuroblastoma, rhabdomyosarcoma, osteosarcoma) and adult cancers (triple negative breast cancer, colon cancer, soft tissue sarcomas). Using this unique panel of patient-derived models we will demonstrate that ATM kinase activation resulting from telomere dysfunction is a common feature of ALT+ cancers (regardless of histology). We will demonstrate that clinical-stage investigational drugs leveraging the high ATM kinase activation in ALT+ cancers (the ATM kinase inhibitor AZD1390 and the p53 activator APR-246) combined with irinotecan have significantly higher activity in ALT+ cancers relative to telomerase+ comparators. For cell lines and xenografts of selected histologies we will determine if AZD1390 can reverse resistance to irinotecan. We hypothesize that ALT+ cancers tolerate ATM activation due to dysfunctional p53, and that p53 restored to functionality by APR-246 will be activated (phosphorylated) by ATM. We will demonstrate that APR-246 (alone or in combination with irinotecan) will be selectively cytotoxic to ALT+ relative to telomerase+ cancer cell lines and xenografts. This project will demonstrate that the unique vulnerability conferred by the dependence of ALT+ cancers cells on ATM kinase is common to ALT+ cancers across a range of cancer histologies. Data from this project will inform development of histology-agnostic clinical trials seeking to enroll patients with ALT+ cancers that are readily identifiable with a robust tumor biomarker.

抽象的端粒是在染色体末端具有 TTAGGG DNA 重复序列的核蛋白，可保护编码 DNA 免受侵蚀和检测为 DNA 损伤。端粒的维持是癌细胞无限增殖所必需的容量。大多数癌症通过激活核糖核蛋白端粒酶来维持其端粒。低或无癌症端粒酶活性通常使用另一种机制来延长端粒，即端粒替代延长 (ALT) 其中端粒通过同源端粒-DNA重组来维持，但其机制仍不清楚明白了。 ALT+ 肿瘤含有染色体外端粒 DNA C 环，（通过独特的 PCR 检测检测到）提供特异性且灵敏的 ALT 生物标志物。我们利用 C 环分析调查了各种童年时期和成人癌症，发现 11 种癌症组织学中 ALT 阳性范围为 10% 至 74%，另外还有 5 种癌症组织学中 1% 至 5% 为 ALT+。无论组织学如何，ALT+ 癌症的临床结果都很差与端粒酶+癌症相比，癌细胞系对 DNA 损伤剂表现出高抵抗力。 ALT 癌症有功能失调的端粒，它提供了独特的脆弱性，可以作为新的治疗靶点。我们最近有研究表明，ALT 神经母细胞瘤中 ATM 激酶的高激活会导致对 DNA 损伤性化疗的耐药性，可以用临床阶段的 ATM 抑制剂 AZD0156 逆转。根据我们的数据，我们假设 ALT+ 癌症具有相同的特征对标准疗法的常见耐药机制和可用于治疗的常见弱点。加强 ALT+ 癌症生物学研究、新治疗靶点的发现和验证，并进行比较跨越一系列组织学的 ALT+ 癌症，我们组装了一大组 ALT+ 患者来源的细胞系 (PDCL) 和患者来源的异种移植物 (PDX) 和比较端粒酶+ PDCL 和 PDX，包括儿科癌症（神经母细胞瘤、横纹肌肉瘤、骨肉瘤）和成人癌症（三阴性乳腺癌、结肠癌、软癌）组织肉瘤）。使用这个独特的患者衍生模型组，我们将证明 ATM 激酶激活端粒功能障碍导致的 ALT+ 癌症的一个共同特征（无论组织学如何）。我们将展示临床阶段研究药物利用 ALT+ 癌症中 ATM 激酶的高激活（ATM 激酶抑制剂 AZD1390 和 p53 激活剂 APR-246) 与伊立替康联合具有显着更高的 ALT+ 活性与端粒酶+比较者相关的癌症。对于选定组织学的细胞系和异种移植物，我们将确定是否 AZD1390 可以逆转伊立替康耐药性。我们假设 ALT+ 癌症能够耐受 ATM 激活，因为功能失调的 p53，以及通过 APR-246 恢复功能的 p53 将被 ATM 激活（磷酸化）。我们将证明 APR-246（单独或与伊立替康联合）相对于 ALT+ 具有选择性细胞毒性端粒酶+癌细胞系和异种移植物。该项目将证明由 ALT+ 癌细胞对 ATM 激酶的依赖性对于一系列癌症组织学中的 ALT+ 癌症来说是常见的。数据该项目的成果将为寻求招募 ALT+ 癌症患者的组织学不可知临床试验的发展提供信息可以通过强大的肿瘤生物标志物轻松识别。