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

• 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
• 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

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 端粒是核蛋白，在染色体的末端具有TTAGGG DNA重复序列，可保护编码DNA免受 侵蚀和检测为DNA损伤。端粒维持对于癌细胞具有无限的增殖所必需 容量。大多数癌症通过激活核糖核蛋白端粒酶维护其端粒。低或没有的癌症 端粒酶活性通常使用另一种机制扩展端粒，端粒的替代性延长（ALT） 其中通过同源端粒-DNA重组维持端粒，但该机制仍然很差 理解。 Alt+肿瘤包含染色体外端粒DNA C圆，该C-Circles（用独特的PCR分析检测） 提供特定敏感的Alt生物标志物。使用C-Circle分析，我们已经调查了各种童年 和成人癌症，发现11种癌症组织学，阳性率从10％到74％，另外5个癌症不等 Alt+的组织学为1-5％。 Alt Cancer的临床结局差，而不管组织学的ALT+如何 癌细胞系相对于端粒酶+癌症表现出对DNA破坏剂的高电阻。 Alt Cancers拥有 功能障碍的端粒，可提供独特的漏洞，可以用作新的治疗靶标。我们最近有 在ALT神经母细胞瘤中显示出高的ATM激酶激活导致对DNA损害化学疗法的抗性 可以使用临床阶段ATM抑制剂AZD0156逆转。根据我们的数据，我们假设Alt+ Cancers共享 对标准疗法的抵抗力和可能利用用于治疗的常见脆弱性的两种常见机制。 为了增强对Alt+癌症生物学的研究，发现和验证了新型治疗靶标，并能够比较 在各种组织学范围内，我们已经组装了一组ALT+患者衍生的细胞系（PDCLS） 以及患者衍生的异种移植物（PDXS）和比较端粒酶+ PDCL和PDX，包括小儿癌 （神经母细胞瘤，横纹肌肉瘤，骨肉瘤）和成年癌（三乳腺癌，结肠癌，软癌 组织肉瘤）。使用这种独特的患者衍生模型面板，我们将证明ATM激酶激活 端粒功能障碍导致的是ALT+癌症的常见特征（无论组织学如何）。我们将证明 该临床阶段的研究药物利用ALT+癌症中高的ATM激酶激活（ATM激酶 抑制剂AZD1390和p53激活剂APR-246）与Irinotecan结合在Alt+的活性明显更高 癌症相对于端粒酶+比较器。对于选定组织学的细胞系和异种移植，我们将确定是否是否 AZD1390可以逆转对伊立替康的抗性。我们假设ALT+癌症耐受ATM激活 功能失调的p53，该p53通过ATM将ATM激活（磷酸化）恢复为功能。我们将 证明APR-246（单独或与Irinotecan联合使用）将选择性地相对于Alt+相对于Alt+ 端粒酶+癌细胞系和异种移植物。该项目将表明，独特的漏洞由 ALT+癌细胞对ATM激酶的依赖性对于跨多种癌症组织学是ALT+癌症共有的。数据 该项目将为组织学临床试验的发展提供信息，以寻求入学Alt+ Cancers的患者 可以通过强大的肿瘤生物标志物易于识别。