Telomeres, telomerase and chemotherapy: Bench to bedside

端粒、端粒酶和化疗：从实验室到床边

• 批准号: 7091068
• 负责人: Jessie L.-S. Au
• 金额: $ 31.22万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2008-04-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091068
• 关键词: 2' -Deoxythymidine; A549; Address; Advanced Malignant Neoplasm; Animals; Antineoplastic Agents; Breast; Cell Aging; Cell Cycle; Cell Cycle Arrest; Cell Fraction; Cell Line; Cell Proliferation; Cell division; Cells; Cessation of life; Characteristics; Chemosensitization; Chromosomes; Clinical; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Computer Simulation; Cultured Tumor Cells; DNA biosynthesis; DNA chemical synthesis; DNA-Directed DNA Polymerase; Data; Development; Disease Progression; Dose; Enzymes; Equilibrium; Fluorouracil; Frequencies; Future; Germ Cells; Goals; Grant; Growth; Hand; Head and neck structure; Human; In Vitro; Kidney; Knock-out; Length; Life Expectancy; Lung; MCF7 cell; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Molecular; Molecular Profiling; Molecular Target; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Paclitaxel; Pancreas; Parents; Patients; Pharmaceutical Preparations; Pharyngeal structure; Phase; Plasma; Play; Property; Prostate; Publishing; RNA; Rate; Research Personnel; Residual state; Resistance; Ribonucleoproteins; Role; Sampling; Somatic Cell; Stem cells; Suggestion; Suramin; Telomerase; Telomerase Inhibitor; Telomerase inhibition; Telomere Maintenance; Telomere Shortening; Testing; Therapeutic; Time; Toxic effect; Translating; Translations; Treatment Protocols; Tumor Burden; Week; Work; base; bench to bedside; cancer therapy; cell growth; chemosensitizing agent; chemotherapy; concept; cytotoxic; cytotoxicity; design; desire; human TERT protein; in vivo; inhibitor/antagonist; intravesical; malignant breast neoplasm; neoplastic cell; novel; pre-clinical; programs; repaired; research clinical testing; resistance mechanism; response; success; telomere; therapeutic target; therapy development; treatment duration; tumor; zidovudine triphosphate

DESCRIPTION (provided by applicant): Telomere shortening occurs during cell division, and results in cell senescence and death when a critical minimum length is reached. Telomere length is usually maintained by telomerase, an enzyme that is present in about 85 percent of human tumors, but seldom in normal somatic cells. This property makes telomerase an attractive therapeutic target; yet no successful telomerase-directed therapy has thus far been developed. A major reason is that pre-existing telomeres in tumor cells usually are of sufficient length to support multiple rounds of cell proliferation, so that telomerase inhibition is not cytotoxic before a lethal tumor burden is reached. The overall goal of the previous grant was to develop a strategy to use telomeres and telomerase as cancer therapeutic target. This goal has been achieved. Briefly, we established simultaneous targeting of telomeres and telomerase as s a useful therapeutic strategy. We found that paclitaxel causes direct damage to telomeres and induces telomerase activity, and that telomerase inhibitors, including hTR antisense and 3'-azido-3' deoxythymidine (AZT), enhanced paclitaxel activity in tumor cells and tumor-bearing animals without enhancing host toxicity. We further found that this strategy only works for chemotherapeutic drugs that damage telomeres and/or induce telomerase and only in tumors that depend on telomerase for telomere repair. Furthermore, the synergy between AZT and paclitaxel was diminished at higher AZT concentrations that are known to cause cell cycle arrest. The goal of the present application is to translate these earlier findings on the novel mechanisms of paclitaxel resistance and synergy between paclitaxel and AZT to useful clinical treatments. Aim 1 examines the generalizability of this strategy and provides additional molecular evidence of the role of telomere/telomerase in paclitaxel activity. Aim 2 will use PD- and computational modeling approaches to translate the preclinical data to find the AZT regimens that deliver to tumors the desired AZTTP levels and the optimal balance between the desired telomerase/telomere effects and the undesired cell cycle blockade effects, in humans. Aim 3, which is to test the strategy of extending the telomerase inhibitor treatment beyond the cytoreductive chemotherapy, may provide a means to control residual tumor cells and to sensitize tumor cells for subsequent chemotherapy. Aim 4 will identify the tumor types with the correct molecular target and response profile (i.e., tumors that depend on telomerase to repair paclitaxel-induced telomere damage and show synergy with AZT). This is necessary even though -85% of human tumors express telomerase because, as we have shown, not all telomerase expressing tumors are dependent on telomerase for telomere maintenance. Collectively, the proposed studies represent a rational therapy development paradigm, designed based on our newly discovered mechanism of paclitaxel resistance and synergy with telomerase inhibitors. Confirmation that the telomerase-mediated resistance is important for paclitaxel will support clinical development of the telomerase/telomere-targeting approach and may yield a novel treatment paradigm that maximizes the therapeutic value of paclitaxel.

描述（由申请人提供）：端粒缩短发生在细胞分裂期间，并在达到临界最小长度时导致细胞衰老和死亡。端粒长度通常由端粒酶维持，端粒酶是一种大约85％的人类肿瘤中的酶，但在正常体细胞中很少。该特性使端粒酶成为有吸引力的治疗靶点；然而，到目前为止，尚未开发成功的端粒酶导向疗法。一个主要原因是，肿瘤细胞中的端粒通常足够长以支撑多发细胞增殖，因此在达到致命的肿瘤负担之前，端粒酶抑制剂不是细胞毒性的。先前赠款的总体目标是制定一种使用端粒和端粒酶作为癌症治疗靶标的策略。这个目标已经实现。简而言之，我们将端粒和端粒酶的同时定位为有用的治疗策略。我们发现，紫杉醇会直接损害端粒并诱导端粒酶活性，并且端粒酶抑制剂（包括HTR抗义和3'-氮杂-3'Dexyphymidine（AZT）），增强型在肿瘤细胞和肿瘤动物中的紫杉醇活性增强而无需增强宿主毒性而没有增强宿主毒性。我们进一步发现，该策略仅适用于损害端粒和/或诱导端粒酶的化学治疗药物，并且仅在依赖端粒型端粒修复的肿瘤中。此外，在较高的AZT浓度下，AZT和紫杉醇之间的协同作用降低，已知会导致细胞周期停滞。本应用的目的是将这些早期的发现转化为紫杉醇和AZT之间的紫杉醇耐药性和协同作用的新机制，为有用的临床治疗。 AIM 1检查了该策略的普遍性，并提供了端粒/端粒酶在紫杉醇活性中的作用的其他分子证据。 AIM 2将使用PD和计算建模方法来翻译临床前数据，以找到向肿瘤传递所需AZTTP水平的AZT方案，以及所需的端粒酶/端粒效应与不希望的细胞周期封锁效应之间的最佳平衡。 AIM 3（即测试将端粒酶抑制剂治疗范围扩展到细胞化学化疗的策略）可能提供了一种控制残留肿瘤细胞并使肿瘤细胞敏化的方法。 AIM 4将以正确的分子靶标和响应特征鉴定肿瘤类型（即依赖端粒酶修复紫杉醇诱导的端粒损伤并与AZT显示协同作用的肿瘤）。这是必要的，即使-85％的人类肿瘤表达端粒酶，因为正如我们所表明的那样，并非所有表达肿瘤的端粒酶都取决于端粒维持的端粒酶。总的来说，拟议的研究代表了一种合理的治疗发展范式，该范例是基于我们新发现的紫杉醇耐药性和与端粒酶抑制剂协同作用的机制。确认端粒酶介导的抗性对于紫杉醇将支持端粒酶/端粒靶向方法的临床发展，并可能产生一种新型的治疗范式，从而最大程度地提高紫杉醇的治疗价值。