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

项目摘要 背景：高级别卵巢浆液性癌（HGSC）患者的治疗选择有限 除了手术和化疗转移性HGSC在很大程度上仍然是不可治愈的，几乎总是 由于其极“冷”的肿瘤微环境（TME），对免疫疗法无反应。成功治愈 这种毁灭性的癌症可能依赖于针对免疫抑制关键驱动因素的新疗法， TME还有待确定。 创新：在临床前模型中有效的药物在转化为疗效方面太常见的失败 在人类恶性肿瘤中的应用需要开发模拟TME的天然环境中的肿瘤的测定。 这项提案利用全人类高通量药物筛选， 首次利用了HGSC恶性腹水的免疫抑制特征。重新利用小- 为寻找HGSC的新型治疗药物，我们设计了一个包含4，292个小分子化合物的定制化合物库， FDA批准的或具有已知作用机制（MOA）的可药用分子， 鉴定了9个最高靶标，包括BTK抑制。迄今为止，BTK抑制剂已被批准作为治疗 血液恶性肿瘤，但尚未在包括卵巢癌（OvCa）在内的许多实体瘤中进行研究。的 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， 患者源性类器官模型作为TME的忠实代表，以确定 用于HGSC治疗的BTK抑制剂。 假设：BTK抑制剂可通过同时激活抗肿瘤免疫来改善HGSC结局 和直接抑制肿瘤生长。 具体目标： 目的1：BTK在HGSC肿瘤细胞中的作用是什么？ 目的2：BTK抑制如何激活HGSC瘤内免疫细胞？ 目的3：BTK抑制剂是否减少体内肿瘤生长？ 影响：这一以患者为中心、假设驱动的提案的成功不仅将推动当前的 了解HGSC中的关键免疫抑制机制，还导致发现新的治疗方法， 小分子靶标和独特的生物标志物。此外，我们的项目可能会提出新的组合 在HGSC背景下，这些新靶点与已上市或临床试验药物的治疗。如果 成功，我们的研究将为HGSC免疫治疗提供一种新的治疗模式。

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.