Inhibition of CaMKK2 sensitizes rectal cancers to radiation therapy

摘要 在美国，结肠癌和直肠癌是美国人诊断出的第三种常见癌症 男人和女人都是。II-III期直肠癌的标准护理是新辅助化疗或放射治疗 短程放疗后行全直肠系膜切除术。然而，对新辅助放射的反应 不同患者的情况有所不同，有些患者的反应很小，10%-30%的患者有病理完全反应。 病理完全缓解与临床结果的改善有关，包括可切除性、括约肌 保存、局部控制和整体生存。因此，使直肠癌变得敏感的新策略 放射治疗在提高病理应答率、改善临床疗效、 并支持新兴的完全新辅助治疗范例和实验性的观察和等待方法。 该项目的长期目标是通过靶向治疗来提高直肠癌的放射治疗效果。 钙/钙调蛋白依赖的蛋白激酶2(CAMKK2)。CAMKK2属于一个家族 参与钙/钙调蛋白(CaM)信号通路并发挥作用的多功能丝氨酸/苏氨酸蛋白激酶 在控制能量平衡、炎症和组织再生方面起着关键作用。已有多项研究报道 用遗传方法或小分子抑制剂STO-609阻断CAMKK2抑制 乳腺癌、前列腺癌和肝癌在体外和体内的生长。此外，在初步研究中，我们发现 STO-609在体外使小鼠结直肠癌有机物对辐射增敏。要在中调查这个问题 体内，我们开创了新的方法来在远端结肠产生孤立的、原发的肿瘤，这种肿瘤可以 通过结肠镜检查并重现人类疾病的组织学。在初步研究中，我们发现 盆腔局部放射有效地抑制了这些肿瘤的生长。这些模型代表了一个重大的进步 与其他常用的结直肠癌小鼠模型相比，这些小鼠发展成许多肿瘤，主要发生在 因此，它不适合研究直肠癌的放射治疗。基于这些 在我们的新发现中，我们假设阻断CAMKK2信号将改善对辐射的反应 建立小鼠直肠癌模型。

Abstract In the United States, colon cancer and rectal cancer are the third most common cancer diagnosed in both men and women. The standard of care for stage II-III rectal cancer is neoadjuvant chemoradiation or short-course radiation followed by total mesorectal excision. However, the response to neoadjuvant radiation varies across patients, with some having minimal response to 10-30% having a pathologic complete response. Pathologic complete response is associated with improved clinical outcomes including resectability, sphincter preservation, local control, and overall survival. Therefore, novel strategies that sensitize rectal cancers to radiation therapy will have great potential to increase pathologic response rates, improve clinical outcomes, and support the emerging total neoadjuvant therapy paradigm and the experimental watch-and-wait approach. The long-term goal of this project is to increase the efficacy of radiation therapy for rectal cancer by targeting calcium/calmodulin-dependent protein kinase kinase 2 (Camkk2). Camkk2 belongs to a family of multifunctional Ser/Thr kinases that participate in the calcium/ calmodulin (CaM) signaling pathway and play a crucial role in controlling energy balance, inflammation and tissue regeneration. Several studies have reported that blocking Camkk2 using genetic approaches or the small molecule inhibitor STO-609 suppresses the growth of breast, prostate and liver cancers in vitro and in vivo. Furthermore, in preliminary studies we found that STO-609 sensitizes mouse colorectal cancer organoids to radiation in vitro. To investigate this question in vivo, we pioneered novel methods to generate solitary, autochthonous tumors in the distal colon that can be monitored with colonoscopy and reproduce the histology of human disease. In preliminary studies, we found that focal pelvic radiation effectively inhibits growth of these tumors. These models represent a major advance over other commonly used colorectal cancer mouse models, which develop many tumors predominantly in the small intestine and are therefore poorly suited to studying radiation therapy of rectal cancer. Based on these findings, we hypothesize that blocking Camkk2 signaling will improve the response to radiation in our novel mouse models of rectal cancer.