Optimal BET inhibitor combination therapies in triple negative breast cancer

三阴性乳腺癌的最佳 BET 抑制剂联合疗法

• 批准号: 10089418
• 负责人: Jennifer Yawei Ge
• 金额: $ 2.65万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089418
• 关键词: Affect; Aftercare; Age; Bar Codes; Basal Cell; Birth; Breast Cancer cell line; Bromodeoxyuridine; CD44 gene; Cell Survival; Cells; Cessation of life; Clinical Trials Design; Combined Modality Therapy; DNA; DNA Library; Diagnosis; Differentiation Antigens; Disease Progression; Epigenetic Process; Evolution; Fatty acid glycerol esters; Growth; Heterogeneity; Immunocompetent; Immunodeficient Mouse; Immunotherapy; In Vitro; Individual; Injections; Label; Lead; Libraries; Mathematics; Measures; Mediating; Methods; Modeling; Mouse Mammary Tumor Virus; Mus; Outcome; PD-L1 blockade; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Population Dynamics; Process; Prognosis; Research; Resistance; Resistance development; S Phase; Sampling; Schedule; Specificity; Stains; Testing; Therapeutic Agents; Treatment Efficacy; Treatment Failure; Treatment Protocols; Treatment outcome; Xenograft procedure; anti-PD-L1 antibodies; cell growth; chemotherapy; drug sensitivity; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; mammary; neoplastic cell; novel therapeutics; pressure; prevent; programmed cell death ligand 1; response; single-cell RNA sequencing; targeted agent; targeted treatment; translational impact; treatment comparison; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor heterogeneity

PROJECT SUMMARY Triple negative breast cancer (TNBC) is a major subtype of breast cancer that is associated with generally poor outcome, younger age at diagnosis, and worse prognosis than other subtypes. It currently has no options for targeted therapy, and chemotherapy remains the only pharmacologic option; thus, better treatments are urgently needed. We recently demonstrated the potential of a class of epigenetic targeted agents, BET inhibitors, as a promising new therapy in TNBC. However, the rapid development of resistance necessitates further study to determine how to effectively administer these drugs and to prevent resistance. Treatment with the prototypical BET inhibitor, JQ1, is known to induce phenotypic changes in cellular state, which may mediate resistance. The high degree of intratumor heterogeneity in TNBC may also contribute to development of resistance and treatment failure. Therefore, a better understanding is needed of how tumor populations are affected by the selective pressures of treatment. Furthermore, effective combination therapies must be developed and their administrations optimized in order achieve a more durable response. I hypothesize that double and triple combination therapies with paclitaxel chemotherapy and PD-L1 immunotherapy, as well as the order in which combinations are administered, will have an effect on treatment efficacy and tumor evolution. In Aim 1, I will investigate population dynamics in response to JQ1 combination therapy with paclitaxel, using TNBC cell lines barcoded with a high-complexity DNA library to track individual subclones during treatment, both in culture and in xenografts in immunodeficient mice. In Aim 2, I will investigate optimal administration of JQ1 with paclitaxel by testing concomitant and sequential therapy in both orders in xenografts with barcoded cells, in order to assess differences in population dynamics between treatment schedules and differences in cellular response with single cell RNA-seq. I will then use EvoSeq, a method to isolate cells from within a population with barcode-level specificity, to retrieve cells with differentially selected barcodes between treatment schedules and examine whether they are predisposed to resistance and whether pretreatment with one drug alters sensitivity to the second drug. In Aim 3, I will characterize changes in heterogeneity that result from the triple combination of JQ1, paclitaxel, and anti-PD-L1 antibody, after testing all single agents, double combinations, and triple combination in MMTV-PyMT cells in immunocompetent mice. The results of this study will lead to a deeper understanding of how intratumor heterogeneity modifies treatment response and establish how to optimally combine BET inhibitors. This research will also have direct translational impact in informing the rational design of clinical trials and, if successful, would lead to improved survival for patients with TNBC.

项目总结 三阴性乳腺癌(TNBC)是乳腺癌的一种主要亚型，与一般较差的 结果，确诊时年龄较小，预后比其他亚型差。它目前没有选择 靶向治疗，化疗仍然是唯一的药物选择；因此，更好的治疗方法是 急需之物。我们最近展示了一类表观遗传靶向制剂BET的潜力。 抑制剂作为一种很有前途的治疗TNBC的新方法。然而，抗药性的快速发展要求 进一步研究以确定如何有效地管理这些药物并防止耐药性。通过以下方式治疗 已知典型的BET抑制剂JQ1可引起细胞状态的表型变化，这可能 调停抵抗。肿瘤内高度的异质性也可能有助于肿瘤的发展。 耐药和治疗失败。因此，需要更好地了解肿瘤种群是如何 受到治疗的选择性压力的影响。此外，有效的联合疗法必须是 发展和优化其行政管理，以实现更持久的应对。我假设 紫杉醇化疗和PD-L1免疫疗法的双重和三联疗法，以及 联合用药的顺序将对治疗效果和肿瘤产生影响 进化论。在目标1中，我将研究JQ1与 紫杉醇，使用用高复杂性DNA文库条形化的TNBC细胞系来追踪单个亚克隆 在治疗期间，无论是在培养中还是在免疫缺陷小鼠的异种移植中。在目标2中，我将研究最优 JQ1联合紫杉醇在异种移植物中的联合和序贯治疗试验 使用条形码细胞，以评估治疗计划和治疗方案之间的种群动态差异 单细胞rna-seq对细胞反应的差异。然后我将使用EvoSeq，这是一种将细胞从 在具有条形码级别特异性的群体中，检索具有不同选择的条形码的单元格 制定治疗计划，并检查他们是否容易产生耐药性，以及是否用 一种药物会改变对第二种药物的敏感性。在目标3中，我将描述导致异质性变化的特征 从JQ1、紫杉醇和抗PD-L1抗体的三重组合中，在测试了所有单药后， 在免疫活性小鼠的MMTV-PYMT细胞中进行联合和三种联合。这项研究的结果 将导致更深入地理解肿瘤内的异质性如何改变治疗反应并建立 如何以最佳方式组合BET抑制剂。这项研究也将在通知中产生直接的翻译影响 合理的临床试验设计，如果成功，将提高TNBC患者的存活率。