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)的治疗选择有限 除了手术和化疗之外。转移性HGSC在很大程度上仍然是无法治愈的，而且几乎总是 对免疫疗法无反应，因为它的肿瘤微环境(TME)极其寒冷。治愈成功 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而无法转化为疗效的药物的常见失败 在人类恶性肿瘤中，需要开发模拟肿瘤在其天然TME环境中的分析方法。 这项提议通过利用全人类、高通量药物筛查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。为了改变小的- 针对HGSC治疗的新分子药物，我们设计了一个包含4,292个小分子化合物的文库 FDA批准的或可与已知作用机制(MOA)一起用药的分子，其筛选已 确定了包括BTK抑制在内的9个顶级靶点。到目前为止，BTK抑制剂已被批准用于治疗 恶性血液病，但在包括卵巢癌(OvCa)在内的许多实体肿瘤中尚未被研究。这个 Proposal利用了携带人类OvCa最频繁突变的新的同基因小鼠模型和 患者衍生的器官模型作为TME的真实代表，以确定TME的疗效和MOA 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的预后 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抑制剂是否能抑制体内肿瘤的生长？ 影响：这项以患者为中心、假设驱动的提案的成功不仅将推动当前的 了解HGSC的关键免疫抑制机制，也有助于发现新的治疗方法 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 这些新靶点的治疗已经上市或在HGSC环境下的临床试验药物中。如果 本研究的成功将为HGSC的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.