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

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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.