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

项目总结 人类乳头瘤病毒(HPV)驱动的癌症是常见的和致命的。没有选择生物标记物， HPV阳性癌症的分子靶向治疗。大多数在最初的放射治疗后病情恶化的人 化疗在3年内死亡，显示出显著的翻译知识缺口和未得到满足的 临床需要。抗PD1免疫检查点疗法(ICT)对复发的HPV+癌症有效，但 缓解率为20%，一年存活率为40%。为了满足对生物标记物的需求- 对于HPV+癌症的驱动治疗，我们测试了721种独特药物在16种HPV+和17种匹配的患者中的疗效 HPV阴性细胞株和已确定的Aurora激酶抑制剂对HPV+比HPV阴性更有效 癌症。我们在体外证明了Aurora激酶抑制导致HPV+细胞株的凋亡。 减少体内HPV+HNSCC患者来源的异种移植瘤的生长。HPV+癌细胞可能是 对极光抑制很敏感，因为它们的Rb表达较低。Rb1丢失和极光抑制是 在多种癌症细胞系和临床前小鼠模型中具有合成致命性。尽管这一机制 这种合成致死性的潜在原因尚不清楚，即在筛选中发现了多个有丝分裂基因。 提示Rb在有丝分裂和基因组稳定性中的作用是这一机制的核心部分。HPV+癌症 可能依赖有丝分裂酶，如极光，以维持有丝分裂的保真度。我们假设极光激活剂 由于Rb丢失导致基因组不稳定，抑制导致HPV+癌症细胞死亡。此外，我们 假设这种癌细胞死亡将刺激cGAS/STIN途径产生I型干扰素 由此产生的免疫原性细胞死亡将导致宿主T细胞参与，并增加对ICT的敏感性。 第二个假设是至关重要的，因为癌症几乎总是对即使是高度有效的药物产生耐药性。 有针对性的治疗，限制了它们的长期益处。相比之下，信息和通信技术在一些国家产生了持久的反应 因此，必须寻求提高信息和通信技术效力的战略。实现我们的长期目标 为了提高HPV阳性癌症的治愈率，我们建议进行机制研究来阐明Rb的作用 极光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阳性小鼠模型中联合应用极光激酶抑制和ICT的实验(目标2)； 利用来自临床试验的组织来识别预测对免疫组合的反应的生物标志物 复发性HPV阳性癌症患者的检查点和极光激酶抑制。我们提议的研究将 有积极的影响，因为它将解决一个重要的问题，即缺乏对复发的根治疗法 HPV+癌症，并可能通过识别合理的ICT来改变目前这些癌症的临床实践范式 以及有针对性的药物组合。

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.