Inhibition of CaMKK2 sensitizes rectal cancers to radiation therapy

摘要 在美国，结肠癌和直肠癌是第三大最常见的癌症， 无论男女II-III期直肠癌的标准治疗是新辅助放化疗或 短程放疗后行全直肠系膜切除然而，对新辅助放疗的反应 不同的患者有不同的反应，有些患者的反应最小，而10-30%的患者的反应是病理性的。 病理完全缓解与临床结局改善相关，包括可切除性、括约肌 保存、局部控制和总体生存。因此，使直肠癌对 放射治疗将具有增加病理反应率，改善临床结果， 并支持新兴的全面新辅助治疗范例和实验观察和等待方法。 该项目的长期目标是通过靶向增加直肠癌放射治疗的疗效。 钙/钙调蛋白依赖性蛋白激酶激酶2（Camkk 2）。Camkk 2属于一个家族， 多功能Ser/Thr激酶参与钙/钙调蛋白（CaM）信号通路， 在控制能量平衡、炎症和组织再生中起着至关重要的作用。一些研究已报告 使用遗传方法或小分子抑制剂STO-609阻断Camkk 2可以抑制 乳腺癌、前列腺癌和肝癌的生长。此外，在初步研究中，我们发现， STO-609在体外使小鼠结肠直肠癌类器官对辐射敏感。为了研究这个问题， 在体内，我们开创了新的方法来产生孤立的，原位肿瘤在远端结肠，可以 通过结肠镜检查进行监测，并再现人类疾病的组织学。在初步研究中，我们发现 盆腔局部放射能有效抑制肿瘤生长这些模型代表了一个重大进步 相比于其他常用的结直肠癌小鼠模型，其主要在结肠中产生许多肿瘤。 因此不适合研究直肠癌的放射治疗。基于这些 研究发现，我们假设阻断Camkk 2信号传导将改善我们的新的辐射反应。 直肠癌的小鼠模型。

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.