Repurposing Bruton's tyrosine kinase (BTK) inhibitors to reverse immunosuppression in high-grade serous ovarian cancer (HGSC)

重新利用布鲁顿酪氨酸激酶 (BTK) 抑制剂来逆转高级别浆液性卵巢癌 (HGSC) 的免疫抑制

• 批准号: 10661823
• 负责人: LAURIE Hollis GLIMCHER
• 金额: $ 8.9万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-07 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10661823
• 关键词: Acceleration; Address; Aftercare; Agammaglobulinaemia tyrosine kinase; Animals; Antitumor Response; Ascites; Biological Assay; Biological Markers; CRISPR/Cas technology; Cell Line; Cells; Clinical; Clinical Trials; Coculture Techniques; Combined Modality Therapy; Custom; Data; Down-Regulation; FDA approved; Failure; Gene Targeting; Genetic; Genetically Engineered Mouse; Growth; Hematologic Neoplasms; Human; Immune; Immunity; Immunosuppression; Immunotherapy; Innate Immune Response; Ions; Knock-out; Libraries; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Marketing; Mediating; Modeling; Molecular Mechanisms of Action; Monitor; Mouse Cell Line; Mutation; Natural Immunity; Neoplasm Metastasis; Operative Surgical Procedures; Organoids; Outcome; Ovarian Serous Adenocarcinoma; Paclitaxel; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Platinum; Pre-Clinical Model; Primary Neoplasm; Principal Investigator; Proteins; Regulation; Resistance; Role; Serous; Signal Pathway; Signal Transduction; Solid Neoplasm; T-Lymphocyte; Testing; Therapeutic; Time; Translating; Tumor Burden; Tumor Immunity; Tumor Suppression; Tumor-infiltrating immune cells; Tyrosine Kinase Inhibitor; Vascular Endothelial Growth Factors; Western Blotting; Work; Writing; adaptive immunity; assay development; c-myc Genes; cancer therapy; cell type; chemotherapy; design; drug sensitivity; drug testing; efficacy evaluation; exhaustion; functional status; genetic approach; high throughput screening; high-throughput drug screening; immune checkpoint blockade; immune function; implantation; improved; in vivo; innovation; malignant ascites; mouse model; neoplastic cell; new combination therapies; new therapeutic target; novel; novel therapeutics; prevent; screening; single-cell RNA sequencing; small molecule; small molecule inhibitor; small molecule therapeutics; success; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

Project Summary Background: Patients with high grade ovarian serous carcinoma (HGSC) have limited therapeutic options beyond surgery and chemotherapy. Metastatic HGSC has remained largely incurable and almost always unresponsive to immunotherapies due to its extremely “cold” tumor microenvironment (TME). Success in curing this devastating cancer will likely rely upon new therapies targeting the crucial drivers of immunosuppression in the TME, yet to be determined. Innovation: The all too common failure of drugs that are efficacious in pre-clinical models to translate to efficacy in human malignancies requires the development of assays that mimic the tumor in its native setting of the TME. This proposal helps bridge that gap by taking advantage of an all-human, high-throughput drug screen that leverages for the first time the immunosuppressive features of HGSC malignant ascites. To repurpose small- molecule drugs for novel therapy of HGSC, we designed a custom compound library containing 4, 292 small molecules either FDA-approved or druggable with a known mechanism of action (MOA), screening of which has identified 9 top targets including BTK inhibition. To date, BTK inhibitors have been approved as a treatment for hematologic malignancies but have not been studied in many solid tumors including ovarian cancer (OvCa). The proposal utilizes both novel syngeneic mouse models carrying the most frequent mutations in human OvCa and a patient-derived organoid model as a faithful representation of the TME to determine the efficacy and MOA of BTK inhibitors for HGSC therapy. Hypothesis: BTK inhibitors can improve HGSC outcomes by simultaneous activation of anti-tumor immunity and direct inhibition of tumor growth. Specific Aims: Aim 1: What is the role of BTK in HGSC tumor cells? Aim 2: How does BTK inhibition activate HGSC intratumoral immune cells? Aim 3: Do BTK inhibitors reduce tumor growth in vivo? Impact: Success in this patient-focused, hypothesis-driven proposal will not only advance the current understanding of key immunosuppressive mechanisms in HGSC, but also lead to discovery of novel therapeutic small molecule targets and unique biomarkers. Additionally, our project may suggest new combinational therapies of these novel targets with already marketed or in clinical trial drugs in the setting of HGSC. If successful, our study will provide a novel treatment paradigm for HGSC immunotherapy.

项目摘要 背景：高级卵巢浆液性癌（HGSC）的患者的治疗选择有限 除了手术和化学疗法之外。转移性HGSC在很大程度上无法治愈，几乎总是 由于其非常“冷”的肿瘤微环境（TME），对免疫疗法没有反应。成功的固化 这种毁灭性的癌症可能会依赖于针对免疫抑制至关重要驱动因素的新疗法 TME，尚未确定。 创新：在临床前模型中有效的药物的所有太常见失败，以转化为有效 在人类的恶性肿瘤中，需要在其本地TME的天然环境中模仿肿瘤的阿萨斯的发展。 该建议通过利用全人类的高通量药物屏幕来帮助弥合差距 HGSC恶性腹水的免疫抑制特征首次利用。复制小型 用于HGSC的新型治疗的分子药物，我们设计了一个定制化合物库，其中包含4，292小型 通过已知的作用机理（MOA）的FDA批准或可吸毒的分子，其筛选的具有 确定了9个主要目标，包括BTK抑制剂。迄今为止，BTK抑制剂已被批准作为治疗 血液学恶性肿瘤，但尚未在包括卵巢癌（OVCA）在内的许多实体瘤中进行研究。这 提案利用了人类OVCA和 患者衍生的类器官模型作为TME的忠实表示，以确定效率和MOA BTK抑制剂用于HGSC治疗。 假设：BTK抑制剂可以通过简单激活抗肿瘤免疫来改善HGSC结果 并直接抑制肿瘤生长。 具体目的： AIM 1：BTK在HGSC肿瘤细胞中的作用是什么？ AIM 2：BTK抑制如何激活HGSC内肿瘤内免疫细胞？ AIM 3：BTK抑制剂是否会减少体内肿瘤的生长？ 影响：以患者为中心的假设驱动的提案的成功不仅会推动当前 了解HGSC中关键免疫抑制机制，但也导致发现新疗法 小分子靶标和独特的生物标志物。此外，我们的项目可能建议新的组合 在HGSC的情况下，这些新型目标的疗法已经销售或临床试验药物。如果 成功的研究将为HGSC免疫疗法提供新的治疗范例。