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

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41，000人被诊断患有结直肠癌。结直肠癌含有导致癌细胞不受控制地生长和分裂的DNA突变。其中一种突变发生在一种名为KRAS的基因中，KRAS是生长和细胞分裂的关键控制器。当突变时，KRAS会锁定在其活性状态，并向细胞发送持续的信号，促进生长和生存。40-45%的结直肠癌患者的肿瘤中存在KRAS突变。这些肿瘤对标准疗法的反应很差，目前正在开发的疗法在治疗中没有任何成功。因此，迫切需要找到新的方法来治疗这种特殊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称为白细胞介素22（IL-22）的分子可能会促进肿瘤的发展。白细胞介素22是结肠中的双刃剑。在正常情况下，它有助于修复结肠内衬细胞的损伤;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突变肿瘤患者中并非如此。似乎IL-22在具有KRAS突变的细胞中与那些没有突变的细胞中具有不同的作用。IL-22与突变的KRAS协同作用，促进癌症进展并缩短生存期。因此，我们已经确定了一个亚组的患者代表约50%的KRAS突变的结直肠癌，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型患者队列中基因表达和生存率的信息。在本研究的第一阶段，我们将尝试更好地了解有和没有KRAS突变的肿瘤中的IL-22信号传导。我们将使用诊断时患者的活检组织和手术切除的肿瘤组织样本来研究白细胞介素22信号传导。本研究的第二阶段将在早期临床试验中研究阻断IL-22信号传导对结直肠癌的影响。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。我们将招募定义的患者亚组，这些患者的肿瘤具有高或低IL-22受体表达，并且具有或不具有KRAS突变。希望被纳入试验的患者将被给予单剂量的抗体，该抗体阻断IL-22途径或促进IL-22产生的分子（例如，称为白细胞介素-23的相关分子）。通过检查治疗前从这些患者身上采集的活检组织与治疗后切除的肿瘤之间的差异，我们将确定治疗是否成功地降低了IL-22信号传导。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，患者的肿瘤表达高水平的白细胞介素22受体和突变的KRAS将最适合IL-22通路blocket.The结果的研究将铺平道路，更大的临床试验使用IL-22通路阻断在特定的分子亚组的结直肠癌。KRAS突变型结直肠癌患者目前尚无有效的治疗选择，他们代表了一组未满足的临床需求。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个子集确定一种可行的治疗选择。

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.