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.

项目概要 背景：高级别卵巢浆液性癌 (HGSC) 患者的治疗选择有限 除了手术和化疗之外，转移性 HGSC 在很大程度上仍然无法治愈，而且几乎总是无法治愈。 由于其极其“冷”的肿瘤微环境（TME）而对免疫疗法无反应。 这种毁灭性的癌症很可能依赖于针对免疫抑制的关键驱动因素的新疗法 TME 尚未确定。 创新：在临床前模型中有效的药物未能转化为疗效的情况非常普遍 在人类恶性肿瘤中，需要开发模拟肿瘤在 TME 天然环境中的检测方法。 该提案通过利用全人类、高通量药物筛选来帮助弥合这一差距。 首次利用 HGSC 恶性腹水的免疫抑制特征来重新利用小细胞。 针对 HGSC 新型疗法的分子药物，我们设计了一个包含 4, 292 个小分子药物的定制化合物库 FDA 批准的分子或具有已知作用机制 (MOA) 的可药物分子，其筛选已完成 确定了包括 BTK 抑制在内的 9 个首要靶标。迄今为止，BTK 抑制剂已被批准作为治疗药物。 血液系统恶性肿瘤，但尚未在包括卵巢癌 (OvCa) 在内的许多实体瘤中进行研究。 该提案利用了携带人类 OvCa 中最常见突变的新型同基因小鼠模型和 源自患者的类器官模型作为 TME 的忠实代表，用于确定疗效和 MOA 用于 HGSC 治疗的 BTK 抑制剂。 假设：BTK 抑制剂可以通过同时激活抗肿瘤免疫来改善 HGSC 结局 并直接抑制肿瘤生长。 具体目标： 目标 1：BTK 在 HGSC 肿瘤细胞中的作用是什么？ 目标 2：BTK 抑制如何激活 HGSC 瘤内免疫细胞？ 目标 3：BTK 抑制剂是否能减少体内肿瘤生长？ 影响：这项以患者为中心、假设驱动的提案的成功不仅将推进当前的 了解 HGSC 的关键免疫抑制机制，同时也导致新疗法的发现 此外，我们的项目可能会提出新的组合。 HGSC If 中已上市或临床试验药物的这些新靶标的治疗。 成功后，我们的研究将为 HGSC 免疫疗法提供一种新的治疗范例。