Combined bromodomain and CDK4/6 inhibition in NUT Carcinoma and other solid tumors

溴结构域和 CDK4/6 联合抑制 NUT 癌和其他实体瘤

• 批准号: 10577265
• 负责人: Michael L. Cheng
• 金额: $ 22.65万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577265
• 关键词: ANXA5 gene; ATAC-seq; Adolescent and Young Adult; Affect; Apoptosis; Area; BRD2 gene; Binding; Biopsy; Biopsy Specimen; Blood specimen; Bromodomain; Bromodomains and extra-terminal domain inhibitor; CDK4 gene; Cancer Therapy Evaluation Program; Carcinoma; Cell Cycle; Cell Line; Cell Proliferation; ChIP-seq; Chemotherapy-Oncologic Procedure; Chest; Chimeric Proteins; Chromatin; Chromatin Remodeling Factor; Clinical; Clinical Trials; Combined Modality Therapy; Correlative Study; Cytotoxic Chemotherapy; Detection; Development; Diagnosis; Disease; Dose; Drug Kinetics; FDA approved; Future; Genomics; Head; Hematologic Neoplasms; Histone Acetylation; Histones; Intuition; Keratin; Laboratories; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Maximum Tolerated Dose; Neck; Oncogenes; Participant; Patients; Pharmacodynamics; Phase; Phase I Clinical Trials; Play; Population; Pre-Clinical Model; Progression-Free Survivals; Proliferation Marker; Protocols documentation; Recommendation; Regimen; Research; Resistance; Retinoblastoma Protein; Role; S-Phase Fraction; Schedule; Science; Serum; Solid; Solid Neoplasm; Squamous Differentiation; Squamous cell carcinoma; Structure; Systemic Therapy; Time; Translating; Treatment Protocols; Tumor Tissue; Undifferentiated; candidate identification; candidate marker; chimeric gene; cohort; combinatorial; design; exome sequencing; histone acetyltransferase; immunohistochemical markers; inhibitor; involucrin; malignant breast neoplasm; novel; peripheral blood; phase 1 study; phase II trial; potential biomarker; promoter; rare cancer; recruit; response; response biomarker; safety assessment; sex; synergism; thymidine kinase 1; transcription factor; transcriptome sequencing; treatment strategy; tumor; tumor initiation; tumorigenic

Project Summary NUT Carcinoma (NC) is an undifferentiated or poorly differentiated squamous cell carcinoma that typically affects the midline structures, including the head, neck, and thoracic areas. NC occurs predominantly in adolescents and young adults of both sexes, a vulnerable and under-recognized cancer population. It is among the most aggressive of all solid malignancies, with most patients having locally advanced or metastatic disease at diagnosis. NC is characterized by the presence of a NUT fusion oncogene (also known as NUTM1), the most common of which is BRD4-NUT. The chimeric genes encode BRD-NUT fusion proteins which retain BRD- encoded bromodomains that bind acetylated histones and recruit chromatin-remodeling complexes. Mechanistically, BRD-NUT fusion proteins appear to exert their pro-tumorigenic effect by blocking differentiation, possibly through sequestering histone acetyltransferase activity. MYC, an oncogene that encodes a transcription factor that plays a central role in tumor initiation and maintenance, has been identified as a key downstream target of BRD4-NUT. BRD4-NUT has been associated with the MYC promoter and is required to maintain MYC expression in NC cell lines. There is no FDA approved therapy or established treatment regimen for NC. Cytotoxic chemotherapy regimens are used for first-line systemic therapy, and subsequent-line treatment remains an area of high unmet need. Several BET inhibitors have been in development as monotherapies for the treatment of both hematologic and solid tumors, and have shown limited clinical activity in NUT carcinoma. More effective strategies are needed and combinations of BET inhibitors with other therapies represent an intuitive next step. Recently, combined BET and CDK4/6 inhibition demonstrated strong synergism in preclinical models of NUT Carcinoma. We are conducting a combination treatment strategy using the BET inhibitor ZEN003694 with the CDK4/6 inhibitor abemaciclib in patients with NC and other solid tumors through the NCI Cancer Therapy Evaluation Program (CTEP) (Protocol #10509). Tumor tissue research biopsies will be obtained, if safely accessible, at baseline, on-treatment, and at progression to characterize changes in cell cycle and proliferation markers, and to explore potential biomarkers of response and resistance to treatment. These include but are not limited to Ki-67, MYC expression, annexin V (apoptosis detection), whole exome sequencing (WES), chromatin analysis (ATAC sequencing) and histone marks profiling (H3K27ac CHIP-seq). Peripheral blood samples will be collected at baseline, during treatment, and at progression to assess thymidine kinase 1 (TK1) activity. Decrease in serum TK activity has been previously described with CDK4/6 inhibition in breast cancer and may correlate with a change in tumor Ki67. If clinical benefit is observed with ZEN003694 and abemaciclib, this will support exploring the combination further in a phase 2 trial.

项目概要 NUT 癌 (NC) 是一种未分化或低分化鳞状细胞癌，通常影响 中线结构，包括头部、颈部和胸部区域。 NC 主要发生于青少年 以及年轻男女，这是一个脆弱且未被充分认识的癌症人群。它是最 所有实体恶性肿瘤均具有侵袭性，大多数患者患有局部晚期或转移性疾病 诊断。 NC 的特征是存在 NUT 融合癌基因（也称为 NUTM1），这是最常见的 其中常见的是BRD4-NUT。嵌合基因编码 BRD-NUT 融合蛋白，保留 BRD- 编码的溴结构域结合乙酰化组蛋白并招募染色质重塑复合物。 从机制上讲，BRD-NUT 融合蛋白似乎通过阻断分化来发挥其促肿瘤作用， 可能通过隔离组蛋白乙酰转移酶活性。 MYC，一种编码转录的癌基因 在肿瘤发生和维持中起核心作用的因子已被确定为关键的下游因子 BRD4-NUT 的靶点。 BRD4-NUT 已与 MYC 启动子相关，并且是维持 MYC 所必需的 NC 细胞系中的表达。目前还没有 FDA 批准的治疗方法或既定的 NC 治疗方案。 细胞毒性化疗方案用于一线全身治疗和后续治疗 仍然是一个需求未得到满足的领域。几种 BET 抑制剂已被开发为单一疗法 血液肿瘤和实体瘤的治疗，并且在 NUT 癌中显示出有限的临床活性。 需要更有效的策略，BET 抑制剂与其他疗法的组合代表了 直观的下一步。最近，BET 和 CDK4/6 联合抑制在临床前表现出强大的协同作用 NUT 癌模型。我们正在使用 BET 抑制剂进行联合治疗策略 ZEN003694 与 CDK4/6 抑制剂 abemaciclib 通过 NCI 治疗 NC 和其他实体瘤患者 癌症治疗评估计划 (CTEP)（方案#10509）。将获得肿瘤组织研究活检， 如果可以安全地获取，则可以在基线、治疗中和进展时表征细胞周期的变化和 增殖标记物，并探索治疗反应和耐药性的潜在生物标记物。这些包括 但不限于Ki-67、MYC表达、annexin V（细胞凋亡检测）、全外显子组测序（WES）、 染色质分析（ATAC 测序）和组蛋白标记分析（H3K27ac CHIP-seq）。外周血 将在基线、治疗期间和进展时收集样本以评估胸苷激酶 1 (TK1) 活动。先前已经描述了乳腺癌中 CDK4/6 抑制可导致血清 TK 活性降低 并且可能与肿瘤 Ki67 的变化相关。如果使用 ZEN003694 和 abemaciclib 观察到临床益处， 这将支持在第二阶段试验中进一步探索该组合。