Pathfinder: Defining interactions between the cytokine IL-22 and oncogenic KRAS as a new therapeutic target in colorectal cancer

探路者：将细胞因子 IL-22 和致癌 KRAS 之间的相互作用定义为结直肠癌的新治疗靶点

• 批准号: MR/N02690X/1
• 负责人: Fiona Powrie
• 金额: $ 119.23万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN02690X%2F1
• 关键词: Pathfinder; Defining; interactions; between; cytokine

Colorectal cancer is the second most common cause of cancer related death in the UK. Each year roughly 41,000 people are diagnosed with colorectal cancer. Colorectal cancers contain DNA mutations that cause the cancer cells to grow and divide uncontrollably. One of these mutations occurs in a gene called KRAS, a key controller of growth and cell division. When mutated, KRAS becomes locked in its active state and sends constant signals into a cell promoting growth and survival. 40-45% of colorectal cancer patients have KRAS mutations in their tumours. These tumours are poorly responsive to standard therapy and no therapies currently in development have shown any success in their treatment. Therefore, there is an urgent need to find new ways to treat patients with this specific type of colorectal cancer.Our studies have provided early evidence that in some patients with KRAS mutant tumours, a molecule secreted by cells of the immune system, called interleukin 22 (IL-22), might be fueling tumour development. Interleukin 22 is a double-edged sword in the colon. Under normal circumstances, it helps to repair damage to the cells lining the colon; in tumours, however, this normally beneficial molecule can promote cancer cell growth and survival. Patients whose tumours have both high levels of the IL-22 receptor and KRAS mutations have a very poor prognosis. This is not the case in patients with KRAS mutant tumours expressing low levels of the interleukin 22 receptor. It seems that IL-22 has different effects in cells that have KRAS mutations versus those that do not. IL-22 synergizes with mutated KRAS to promote cancer progression and shorten survival. Therefore, we have identified a subgroup of patients representing approximately 50% of KRAS mutant colorectal cancers, whom we believe may benefit from therapeutic strategies designed to neutralize IL-22. All of our data thus far has come from retrospectively assessing information on gene expression and survival in large patient cohorts. In the first phase of this study, we will try to better understand IL-22 signaling in tumours with and without KRAS mutations. We will use biopsies taken from patients at the time of diagnosis and tissue samples from their surgically resected tumours to investigate interleukin 22 signaling. The second phase of this study will investigate the effects of blocking IL-22 signaling in colorectal cancer in an early phase clinical trial. This type of trial is called a Phase 0 window trial which takes advantage of the window of time between patient diagnosis and when they have surgery for tumour removal. We will recruit defined subgroups of patients whose tumours either have high or low IL-22 receptor expression and have or do not have KRAS mutations. Patients who wish to be included in the trial will be given a single dose of an antibody that blocks either the IL-22 pathway or molecules that promote IL-22 production (e.g. a related molecule named interleukin-23). By examining the differences between the biopsies taken from these patients before the treatment and their resected tumour after the treatment, we will determine whether the treatment successfully reduced IL-22 signaling. Furthermore, we will identify patient subgroups in which IL-22 blockade is most effective. Based on our existing data, we expect that patients whose tumours express high levels of the interleukin 22 receptor and are mutant for KRAS will be most amenable to IL-22 pathway blockade.The results of this study will pave the way to larger clinical trials using IL-22 pathway blockade in specific molecular subgroups of colorectal cancer. There are currently no effective therapeutic options for KRAS mutant colorectal cancer patients and they represent a group of unmet clinical need. However, using a novel approach of blocking an immune signal in the context of KRAS mutation, we hope to identify a viable therapeutic option for a subset of these patients.

结直肠癌是英国癌症相关死亡的第二大常见原因。每年大约有4.1万人被诊断患有结肠直肠癌。结直肠癌含有DNA突变，导致癌细胞不受控制地生长和分裂。其中一种突变发生在KRAS基因上，KRAS是生长和细胞分裂的关键控制因子。当发生突变时，KRAS被锁定在其活跃状态，并向细胞发送持续的信号，促进细胞的生长和生存。40-45%的结直肠癌患者肿瘤中存在KRAS突变。这些肿瘤对标准治疗反应不佳，目前正在开发的治疗方法没有显示出任何成功的治疗效果。因此，迫切需要寻找新的方法来治疗这种特定类型的结直肠癌患者。我们的研究提供了早期证据，表明在一些KRAS突变肿瘤患者中，免疫系统细胞分泌的一种叫做白细胞介素22 （IL-22）的分子可能会促进肿瘤的发展。白细胞介素22在结肠中是一把双刃剑。在正常情况下，它有助于修复结肠内壁细胞的损伤；然而，在肿瘤中，这种通常有益的分子可以促进癌细胞的生长和存活。肿瘤同时具有高水平IL-22受体和KRAS突变的患者预后非常差。在表达低水平白细胞介素22受体的KRAS突变肿瘤患者中，情况并非如此。似乎IL-22在有KRAS突变的细胞和没有KRAS突变的细胞中有不同的作用。IL-22与突变的KRAS协同促进癌症进展并缩短生存期。因此，我们确定了一个亚组患者，约占KRAS突变型结直肠癌的50%，我们认为他们可能受益于旨在中和IL-22的治疗策略。到目前为止，我们所有的数据都来自于回顾性评估大量患者群体的基因表达和生存信息。在本研究的第一阶段，我们将尝试更好地了解IL-22信号在有和没有KRAS突变的肿瘤中。我们将使用诊断时患者的活检和手术切除肿瘤的组织样本来研究白细胞介素22信号。本研究的第二阶段将在早期临床试验中研究阻断IL-22信号在结直肠癌中的作用。这种类型的试验被称为0期窗口试验，它利用了患者诊断和手术切除肿瘤之间的时间窗口。我们将招募肿瘤具有高或低IL-22受体表达，具有或不具有KRAS突变的确定亚组患者。希望被纳入试验的患者将被给予单剂量抗体，该抗体可以阻断IL-22途径或促进IL-22产生的分子（例如一种名为白介素-23的相关分子）。通过检查这些患者在治疗前和治疗后切除肿瘤的活检之间的差异，我们将确定治疗是否成功地降低了IL-22信号。此外，我们将确定IL-22阻断最有效的患者亚组。根据我们现有的数据，我们预计那些肿瘤表达高水平的白介素22受体和KRAS突变的患者将最容易受到IL-22通路阻断。这项研究的结果将为在结直肠癌的特定分子亚群中使用IL-22通路阻断进行更大规模的临床试验铺平道路。目前对于KRAS突变型结直肠癌患者没有有效的治疗选择，他们代表了一组未被满足的临床需求。然而，在KRAS突变的背景下，使用一种阻断免疫信号的新方法，我们希望为这些患者的一部分确定一种可行的治疗选择。

项目成果

The Interleukin 22 Pathway Interacts with Mutant KRAS to Promote Poor Prognosis in Colon Cancer

白介素 22 通路与突变 KRAS 相互作用导致结肠癌预后不良

• DOI: 10.5167/uzh-207864
• 发表时间: 2020
• 作者: McCuaig, Sarah

Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease.

• DOI: 10.1038/nm.4307
• 发表时间: 2017-05
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: West NR;Hegazy AN;Owens BMJ;Bullers SJ;Linggi B;Buonocore S;Coccia M;Görtz D;This S;Stockenhuber K;Pott J;Friedrich M;Ryzhakov G;Baribaud F;Brodmerkel C;Cieluch C;Rahman N;Müller-Newen G;Owens RJ;Kühl AA;Maloy KJ;Plevy SE;Oxford IBD Cohort Investigators;Keshav S;Travis SPL;Powrie F
• 通讯作者: Powrie F

Fusobacterium nucleatum, rectal cancer and radiotherapy.

有核梭杆菌、直肠癌和放射治疗。

• DOI: 10.1016/j.annonc.2020.06.019
• 发表时间: 2020
• 期刊: official journal of the European Society for Medical Oncology
• 作者: Mann EH

IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies.

• DOI: 10.1038/s41591-021-01520-5
• 发表时间: 2021-11
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Friedrich M;Pohin M;Jackson MA;Korsunsky I;Bullers SJ;Rue-Albrecht K;Christoforidou Z;Sathananthan D;Thomas T;Ravindran R;Tandon R;Peres RS;Sharpe H;Wei K;Watts GFM;Mann EH;Geremia A;Attar M;Oxford IBD Cohort Investigators;Roche Fibroblast Network Consortium;McCuaig S;Thomas L;Collantes E;Uhlig HH;Sansom SN;Easton A;Raychaudhuri S;Travis SP;Powrie FM
• 通讯作者: Powrie FM