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: 9538367
• 负责人: Jennifer Yawei Ge
• 金额: $ 3.55万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9538367
• 关键词: Affect; Aftercare; Age; Antibodies; 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; Mammary gland; Mathematics; Measures; Mediating; Methods; Modeling; Mouse Mammary Tumor Virus; Mus; Outcome; PDCD1LG1 gene; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Population Dynamics; Process; 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; cell growth; chemotherapy; drug sensitivity; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; neoplastic cell; novel therapeutics; outcome forecast; pressure; prevent; response; single-cell RNA sequencing; targeted agent; targeted treatment; translational impact; 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.

项目概要 三阴性乳腺癌 (TNBC) 是乳腺癌的一个主要亚型，与普遍贫困有关。 与其他亚型相比，其结果、诊断年龄更小、预后更差。目前没有选项 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。我们最近展示了一类表观遗传靶向药物 BET 的潜力 抑制剂，作为 TNBC 的一种有前途的新疗法。然而，耐药性的迅速发展需要 进一步研究以确定如何有效地施用这些药物并防止耐药性。治疗用 已知原型 BET 抑制剂 JQ1 会诱导细胞状态的表型变化，这可能 调解阻力。 TNBC 的高度肿瘤内异质性也可能有助于发展 耐药性和治疗失败。因此，需要更好地了解肿瘤群体的情况 受治疗选择压力的影响。此外，有效的联合疗法必须 制定并优化其管理，以实现更持久的应对措施。我假设 紫杉醇化疗和 PD-L1 免疫疗法的双重和三重联合疗法，以及 联合用药的顺序将对治疗效果和肿瘤产生影响 进化。在目标 1 中，我将研究 JQ1 联合疗法的群体动态 紫杉醇，使用带有高复杂性 DNA 库条形码的 TNBC 细胞系来追踪单个亚克隆 在治疗期间，无论是在培养物还是在免疫缺陷小鼠的异种移植物中。在目标 2 中，我将研究最优 通过在异种移植物中测试两种顺序的伴随治疗和序贯治疗来给予 JQ1 和紫杉醇 与条形码细胞，以评估治疗方案和治疗方案之间群体动态的差异 单细胞 RNA-seq 的细胞反应差异。然后我将使用 EvoSeq，一种从细胞中分离细胞的方法 在具有条形码水平特异性的群体内，检索具有差异选择条形码的细胞 治疗计划并检查他们是否容易产生耐药性以及是否进行过预处理 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 来自 JQ1、紫杉醇和抗 PD-L1 抗体的三重组合，在测试所有单药后，双倍 免疫活性小鼠的 MMTV-PyMT 细胞中的组合和三重组合。本研究结果 将导致更深入地了解肿瘤内异质性如何改变治疗反应并建立 如何最佳地组合 BET 抑制剂。这项研究还将对信息产生直接的转化影响 临床试验的合理设计，如果成功，将提高 TNBC 患者的生存率。