Inhibition of CaMKK2 sensitizes rectal cancers to radiation therapy

CaMKK2 的抑制使直肠癌对放射治疗敏感

基本信息

批准号：
10312803
负责人：
Chang-Lung Lee
金额：
$ 22.13万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312803
关键词：
Ablation Applications Grants CRISPR/Cas technology Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Calmodulin Cancer Model Cancer Patient Clinical Colon Colon Carcinoma Colonoscopy Colorectal Cancer Data Distal Family Gastrointestinal tract structure Genetic Goals Growth Histology In Vitro In complete remission Inflammation Malignant neoplasm of liver Malignant neoplasm of prostate Methods Modeling Monitor Mus Neoadjuvant Therapy Organoids Outcome Pathologic Patients Pelvis Pharmacology Phosphotransferases Play Radiation Radiation therapy Radiobiology Rectal Cancer Reporting Resectable Role Signal Pathway Signal Transduction Small Intestines Sphincter Testing Total Mesorectal Excision United States Woman Work Xenograft procedure base cancer diagnosis cancer radiation therapy chemoradiation energy balance genetic approach human disease improved in vivo inhibitor malignant breast neoplasm men mouse model novel novel strategies organoid transplantation patient response preservation radiation response response small molecule inhibitor standard of care tissue regeneration transplant model tumor tumor growth

项目摘要

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.

抽象的在美国，结肠癌和直肠癌是第三大常见癌症男性和女性。 II-III 期直肠癌的标准治疗是新辅助放化疗或短程放疗后进行全直肠系膜切除。然而，对新辅助放疗的反应不同患者的反应不同，有些患者的反应很小，只有 10-30% 的患者出现病理学完全反应。病理完全缓解与临床结果的改善相关，包括可切除性、括约肌保存、局部控制和总体生存。因此，使直肠癌敏感的新策略放射治疗将具有提高病理反应率、改善临床结果的巨大潜力，并支持新兴的全面新辅助治疗范式和实验性观察等待方法。该项目的长期目标是通过靶向治疗来提高直肠癌放射治疗的疗效钙/钙调蛋白依赖性蛋白激酶激酶 2 (Camkk2)。 Camkk2 属于以下家族参与钙/钙调蛋白 (CaM) 信号通路并发挥作用的多功能 Ser/Thr 激酶在控制能量平衡、炎症和组织再生中发挥着至关重要的作用。多项研究报道使用遗传方法或小分子抑制剂 STO-609 阻断 Camkk2 可抑制乳腺癌、前列腺癌和肝癌的体外和体内生长。此外，在初步研究中我们发现 STO-609 使小鼠结直肠癌类器官对体外辐射敏感。为了调查这个问题在体内，我们开创了在远端结肠中产生孤立的本土肿瘤的新方法，该肿瘤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，我们发现局灶性骨盆放疗可有效抑制这些肿瘤的生长。这些模型代表了重大进步与其他常用的结直肠癌小鼠模型相比，这些模型主要在结直肠癌中产生许多肿瘤小肠，因此不适合研究直肠癌的放射治疗。基于这些研究结果表明，我们假设阻断 Camkk2 信号传导将改善我们小说中对辐射的反应直肠癌小鼠模型。