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

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 SPORE 项目 #4 的目标是开发和评估乳腺癌 SPORE 的转化潜力 我们开发的药物可以强制端粒酶干扰乳腺癌。该项目重点关注 临床应用新策略的开发：将活性端粒酶的作用转向乳房 癌细胞。在当前的融资周期中，我们已经成功证明了低门槛 突变模板端粒酶 RNA (MT-hTer) 基因在人乳腺癌细胞中的表达就足够了 对这些细胞具有有效的杀伤和生长抑制作用。 MT-hTer 作用产生的端粒 对细胞具有“毒性”，诱导强烈的细胞凋亡反应。此外，在之前的 SPORE 资助期间 在此期间，布莱克本实验室对端粒酶的研究产生的新科学也导致了两个] 意想不到的发现：首先，通过核酶或RNA简单地降低内源性端粒酶水平 靶向方法迅速降低了癌症的可能性。具体来说，我们发现降低整体端粒酶 降低体内癌细胞的转移潜力，并迅速抑制乳腺癌和其他肿瘤的生长 体外癌细胞。其次，MT-hTer 表达诱导的细胞死亡占主导地位，不需要 p53 或 pRb 检查点通路。基于这些发现，我们随后证明，结合表达式 MT-hTer 与针对癌细胞内源性 WT-hTER 的小干扰 RNA 协同增加 MT-hTer 杀死癌细胞的效力。具体如下 旨在将这项工作带入临床的目的是： #1 进一步测试并表征 先前开发的免疫脂质体（“ILS”）由 Her2 靶向抗体组成，开发于 SPORE Project 3 包含 MT-hTer/抗 hTER siRNA 构建体（“MT-Rx”剂）。为了监控 MT-Rx 疗效我们将使用药物反应的相关生物标志物，适合早期临床 试验。 #2 识别基于端粒/端粒酶的生物标志物模式预测细胞凋亡反应 抗癌治疗和特定 MT-Rx 治疗。我们将确定乳腺癌的子集 使用 (i) 一组 60 个乳腺癌细胞系对现有疗法和“MT-Rx”最敏感 按基因组和表达谱、端粒维持状态和其他临床相关分组 (ii) 患者来源的原发性乳腺癌细胞，包括干细胞/祖细胞系；塔 针对已确定的最敏感的患者亚群。 ＃3。验证并优化分析 肿瘤和活检标本上端粒酶和端粒状态的生物标志物，目的是验证] 这些测定按照 CLIA 规定在 CLIA 认证的实验室进行，这样结果就可以用于临床。） 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 并评估 MT-Rx 药物在啮齿动物模型中的初步毒理学靶向全身递送。