Harnessing Aurora kinase inhibition‐induced cell death to enhance immunotherapy in HPV‐driven cancers

项目摘要 人乳头瘤病毒（HPV）驱动的癌症是常见的和致命的。没有选择的生物标记， HPV+癌症的分子靶向治疗。大多数在最初的放射治疗后进展的患者 化疗在3年内死亡，这表明存在重大的转化知识差距和未满足的 临床需要抗PD 1免疫检查点疗法（ICT）对复发性HPV+癌症有效，但 缓解率<20%，一年生存率<40%。为了解决生物标志物的未满足需求- 在HPV+癌症的驱动疗法中，我们测试了721种独特药物在16种HPV+和17种匹配的 HPV阴性细胞系，并确定Aurora激酶抑制剂在HPV+中比HPV阴性更有效 癌的我们证明了Aurora激酶抑制导致体外HPV+细胞系的凋亡， 在体内减少HPV+ HNSCC患者来源的异种移植肿瘤的生长。HPV+癌细胞可能是 对Aurora抑制敏感，因为它们的低Rb表达。RB 1损失和极光抑制是 在多种癌细胞系和临床前小鼠模型中，尽管机制 这种合成致死性的潜在原因尚不清楚，事实上，在筛选中鉴定出了多个有丝分裂基因， 表明Rb在有丝分裂和基因组稳定性中的作用是该机制的核心部分。HPV+癌症 可能依赖于有丝分裂激酶如Aurora来维持有丝分裂的保真度。我们假设极光激酶 由于Rb缺失诱导的基因组不稳定性，抑制导致HPV+癌症中的细胞死亡。而且我们 假设这种癌细胞死亡将刺激cGAS/STING途径产生I型干扰素 并且所产生的免疫原性细胞死亡将导致宿主T细胞接合和对ICT的敏感性增加。 这第二个假设是至关重要的，因为癌症几乎总是对即使是非常有效的 靶向治疗，限制了其长期益处。相比之下，信息和通信技术在一些国家产生了持久的反应。 患者，因此必须寻求提高ICT功效的策略。为了实现我们的长期目标 为了提高HPV+癌症患者的治愈率，我们提出了机制研究来阐明Rb的作用， 在Aurora激酶抑制介导的癌细胞死亡中缺失诱导的基因组不稳定性（Aim 1）;体内 在HPV+鼠模型中结合Aurora激酶抑制和ICT的实验（Aim 2）;以及 利用来自临床试验的组织来鉴定生物标志物， 检查点和Aurora激酶抑制在复发性HPV+癌症患者中的作用。我们的研究计划将 有积极的影响，因为它将解决一个重要的问题，缺乏治愈性治疗复发性 HPV+癌症，并可能通过确定合理的ICT来改变这些癌症的当前临床实践模式 和靶向药物组合。

PROJECT SUMMARY Human papillomavirus (HPV)-driven cancers are common and lethal. There are no biomarker-selected, molecular targeted therapies for HPV+ cancers. Most of those who progress after initial therapy with radiation and chemotherapy die within 3 years, demonstrating a significant translational knowledge gap and an unmet clinical need. Anti-PD1 immune checkpoint therapy (ICT) is effective for recurrent HPV+ cancers, but with response rates of <20% and a one-year survival rate of <40%. To address the unmet need for biomarker- driven therapy for HPV+ cancers, we tested the efficacy of 721 unique drugs in 16 HPV+ and 17 matched HPV-negative cell lines and identified Aurora kinase inhibitors as more effective in HPV+ than HPV negative cancers. We demonstrated that Aurora kinase inhibition leads to apoptosis in HPV+ cell lines in vitro and reduced the growth of an HPV+ HNSCC patient-derived xenograft tumor in vivo. HPV+ cancer cells may be sensitive to Aurora inhibition because of their low Rb expression. RB1 loss and Aurora inhibition are synthetically lethal in a variety of cancer cell lines and preclinical mouse models. Although the mechanism underlying this synthetic lethality is unknown, the fact that multiple mitotic genes were identified in screens suggests that Rb's roles in mitosis and genomic stability are a central part of this mechanism. HPV+ cancers may rely on mitotic kinases such as Aurora to maintain mitotic fidelity. We hypothesize that Aurora kinase inhibition results in cell death in HPV+ cancers due to Rb loss-induced genomic instability. Furthermore, we hypothesize that this cancer cell death will stimulate the cGAS/STING pathway producing type I interferons and the resulting immunogenic cell death will lead to host T-cell engagement and increased sensitivity to ICT. This second hypothesis is crucial because cancers nearly always develop resistance to even highly effective targeted therapies, limiting their long-term benefits. In contrast, ICT results in durable responses in some patients, making it imperative to seek strategies that enhance the efficacy of ICT. To meet our long-term goal of improving cure rates for those with HPV+ cancer, we propose mechanistic studies to elucidate the role of Rb loss-induced genomic instability in Aurora kinase inhibition mediated cancer cell death (Aim 1); in vivo experiments with the combination of Aurora kinase inhibition and ICT in HPV+ murine model (Aim 2); and to leverage tissue from a clinical trial to dentify biomarkers predicting response to the combination of immune checkpoint and Aurora kinase inhibition in patients with recurrent HPV+ cancers. Our proposed research will have a positive impact because it will address an important problem, the lack of curative therapy for recurrent HPV+ cancers, and may shift current clinical practice paradigms for these cancers by identifying rational ICT and targeted drug combinations.