Breast Cancer Therapeutic Agents Based on Telomerase Misfunction

基于端粒酶功能障碍的乳腺癌治疗剂

• 批准号: 7384761
• 负责人: ELIZABETH H BLACKBURN
• 金额: $ 14.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7384761
• 关键词: Address; Amplifiers; Antibodies; Antineoplastic Agents; Apoptosis; Apoptotic; Archives; Biological; Biological Assay; Biological Markers; Biopsy Specimen; Breast; Breast Cancer Cell; Breast Cancer Model; Cancer cell line; Catalytic RNA; Cell Death; Cell Line; Cells; Characteristics; Chest Wall Disorder; Clinic; Clinical; Clinical Trials; Data; Development; Drug Formulations; ERBB2 gene; End Point; Freezing; Functional disorder; Funding; Genes; Genomics; Goals; Gray unit of radiation dose; Growth; Guanosine Monophosphate; Immunoliposome; In Vitro; Laboratories; Laboratory Research; Length; Libraries; Malignant Neoplasms; Mammary Neoplasms; Measures; Methods; Modeling; Molecular; Molecular Profiling; Monitor; Neoplasm Metastasis; Paraffin Embedding; Pathway interactions; Patients; Pattern; Performance; Principal Investigator; RNA; RNA Interference; Regulation; Reproduction spores; Rodent; Rodent Model; Sampling; Science; Series; Small Interfering RNA; Staging; Stem cells; System; TP53 gene; Telomerase; Telomerase RNA Component; Telomere Maintenance; Testing; Therapeutic; Therapeutic Agents; Tissue Sample; Toxic Actions; Toxicology; Translating; Translations; Validation; Work; Xenograft Model; Xenograft procedure; anticancer treatment; base; cancer cell; cancer therapy; clinical application; drug sensitivity; functional status; high throughput screening; in vivo; killings; malignant breast neoplasm; mouse model; mutant; nanoparticle; neoplastic cell; programs; research clinical testing; response; scale up; seal; stem; telomere; tumor; vector; Address; Amplifiers; Antibodies; Antineoplastic Agents; Apoptosis; Apoptotic; Archives; Biological; Biological Assay; Biological Markers; Biopsy Specimen; Breast; Breast Cancer Cell; Breast Cancer Model; Cancer cell line; Catalytic RNA; Cell Death; Cell Line; Cells; Characteristics; Chest Wall Disorder; Clinic; Clinical; Clinical Trials; Data; Development; Drug Formulations; ERBB2 gene; End Point; Freezing; Functional disorder; Funding; Genes; Genomics; Goals; Gray unit of radiation dose; Growth; Guanosine Monophosphate; Immunoliposome; In Vitro; Laboratories; Laboratory Research; Length; Libraries; Malignant Neoplasms; Mammary Neoplasms; Measures; Methods; Modeling; Molecular; Molecular Profiling; Monitor; Neoplasm Metastasis; Paraffin Embedding; Pathway interactions; Patients; Pattern; Performance; Principal Investigator; RNA; RNA Interference; Regulation; Reproduction spores; Rodent; Rodent Model; Sampling; Science; Series; Small Interfering RNA; Staging; Stem cells; System; TP53 gene; Telomerase; Telomerase RNA Component; Telomere Maintenance; Testing; Therapeutic; Therapeutic Agents; Tissue Sample; Toxic Actions; Toxicology; Translating; Translations; Validation; Work; Xenograft Model; Xenograft procedure; anticancer treatment; base; cancer cell; cancer therapy; clinical application; drug sensitivity; functional status; high throughput screening; in vivo; killings; malignant breast neoplasm; mouse model; mutant; nanoparticle; neoplastic cell; programs; research clinical testing; response; scale up; seal; stem; telomere; tumor; vector

The goal of UCSF Breast Cancer SPORE Project #4 is to develop and assess the translational potential of agents we have developed that force telomerase interference in breast cancer. This Project focuses on exploitation for clinical use of a new strategy: to turn the action of active telomerase against the breast cancer cells. In this current funding cycle, we have successfully demonstrated that a low threshold of expression of mutant-template telomerase RNA (MT-hTer) genes in human breast cancer cells is sufficient for a potent killing and growth inhibitory effect on these cells. The telomeres that result from MT-hTer action are "toxic" to cells, inducing a robust apoptotic response. Additionally, during the previous SPORE funding period, new science arising from the Blackburn laboratory's research on telomerase also led to two] unanticipated discoveries: first, that simply decreasing the endogenous telomerase level by ribozyme or RNA targeting methods rapidly decreased cancer potential. Specifically, we found that lowering overall telomerase diminishes the metastatic potential of cancer cells in vivo, and rapidly inhibited the growth of breast and other cancer cells in vitro. Second, cell death induced by MT-hTer expression is dominant and does not require the p53 or pRb checkpoint pathways. Based on these findings, we then showed that combining the expression of MT-hTer with small interfering RNA directed against the endogenous WT-hTER of cancer cells synergistically increases the potency of the MT-hTer effects in killing cancer cells. The following Specific Aims, which have the goal of bringing this work to the clinic, are to: #1 Further test and characterize the previously developed immunoliposome ("ILS") constituted with Her2-targeting antibody¿developed in SPORE Project 3¿containing the MT-hTer/anti-hTER siRNA construct ("MT-Rx" agent). In order to monitor MT-Rx efficacy we will use relevant biomarkers of response to the agent, suitable for early stage clinica trials. #2 Identify telomere/telomerase-based biomarker patterns predictive of apoptotic response t anticancer treatments and to specific MT-Rx therapy. We will identify the subset(s) of breast cancers that wil be most responsive to existing therapies and to "MT-Rx" using (i) a panel of 60 breast cancer cell line grouped by genomic and expression profiling, telomere maintenance status and other clinically relevan characteristics and (ii) patient-derived primary breast cancer cells, including stem/progenitor cell lines; tha targets the most sensitive patient subpopulation, as identified. #3. Validate and optimize the assays fo biomarkers of telomerase and telomere status on tumor and biopsy specimens, with the goal of validating] these assays per CLIA regulations in a CLIA certified laboratory such that the results can be used clinically.) Toward translation of MT-Rx, we will finalize the product configuration, perform initial manufacturing seal up, and evaluate initial toxicology targeted systemic delivery of MT-Rx agent in rodent models.

UCSF乳腺癌孢子项目＃4的目标是开发和评估翻译的潜力 我们已经开发了这种力对乳腺癌中的端粒酶干扰。这个项目重点 用于临床使用新策略的剥削：将主动端粒酶对乳房的作用转动 癌细胞。在当前的筹资周期中，我们成功证明了 人乳腺癌细胞中突变型 - themplate端粒酶RNA（MT-hter）基因的表达就足够了 为了对这些细胞产生潜在的杀伤和生长抑制作用。由Mt-thter动作产生的端粒 对细胞“有毒”，诱导强大的凋亡反应。此外，在以前的孢子资金中 时期，布莱克本实验室对端粒酶的研究引起的新科学也导致了两项] 意外发现：首先，仅通过核酶或RNA降低内源性端粒酶水平 靶向方法迅速降低了癌症的潜力。具体来说，我们发现降低整体端粒酶 减少癌细胞在体内的转移潜力，并迅速抑制乳房和其他 体外癌细胞。其次，由mt饮用的细胞死亡占主导地位，不需要 p53或PRB检查点途径。基于这些发现，我们表明将表达式结合在一起 用小干扰RNA针对癌细胞的内源性WT-thter的小型干扰RNA 协同地增加了杀死癌细胞的MT饮用作用的效力。以下特定 目标是将这项工作带到诊所的目标是：＃1进一步测试并表征 以前开发的免疫脂体（“ ILS”）是由Her2靶向抗体构成的 孢子项目3“含有MT/抗抗螺旋体的siRNA构建体（“ MT-RX”代理）。为了监视 MT-RX有效性我们将使用对代理的反应的相关生物标志物，适用于早期临床 试验。 ＃2识别基于端粒/端粒酶的生物标志物模式可预测凋亡反应t 抗癌治疗和特定的MT-RX治疗。我们将确定乳腺癌的子集 使用（i）一个60乳腺癌细胞系的面板对现有疗法和“ MT-RX”的反应最快 通过基因组和表达分析，端粒维持状态和其他临床相关的分组 特征和（ii）患者衍生的原发性乳腺癌细胞，包括茎/祖细胞系； tha 靶向最敏感的患者亚群。 ＃3。验证和优化fo的测定法 在肿瘤和活检标本上的端粒酶和端粒状态的生物标志物，目的是验证] 这些在CLIA认证实验室中的CLIA法规的测定法，以便可以在临床上使用结果。） 为了翻译MT-RX，我们将最终确定产品配置，执行初始制造密封 向上并评估啮齿动物模型中MT-RX药物的最初毒理学靶向系统递送。