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

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.

Inflammation driven by the IL-23/Th17 cell axis is related to poor outcome in colorectal cancer. Cytokines produced during Th17 responses, such as IL-22, promote CRC development in animal models by acting directly on intestinal epithelial cells to promote growth and survival.

The KRAS oncogene is mutated in roughly 45% of colorectal cancer. No targeted therapies currently in development have shown any activity in KRAS mutant CRC and finding novel approaches is a high priority. The available literature suggests that KRAS mutations have little prognostic impact, but our recent studies have shown that among tumours with evidence of heightened IL-22 signalling, KRAS mutations are strongly associated with poor clinical outcome. (McCuaig et al., submitted). Specifically, using tumour transcriptomic datasets totalling nearly 2000 patients (GSE39582, PETACC3, TCGA, ALMAC), we have identified that in patients with high tumoural expression of either or both subunits of the heterodimeric IL-22 receptor (IL22RA1, IL10RB), KRAS mutation dramatically worsens prognosis. In contrast, KRAS has no prognostic relevance in tumours with low expression of IL-22 receptor subunits. Based on this data we hypothesize that modulation of the IL-22 pathway in IL22RA1-high, KRAS mutant tumours may have therapeutic benefit.

Though attractive as a possible therapeutic target for CRC, direct evidence supporting a tumourigenic role for IL-22 in humans is lacking. Furthermore, as KRAS is widely considered an "undruggable" target, methods of improving clinical outcome for patients with KRAS-mutant CRC are urgently needed. We will address both knowledge gaps by studying the role of IL-22 signalling in KRAS wild type versus mutant CRC in order to 1) establish the functional relevance of IL-22 signalling in human CRC; and 2) test the biological impact of IL-22 or IL-23 blockade in molecularly stratified CRC patient subsets in a Phase 0 window trial.

Colorectal cancer is the second most common cause of cancer related death in the UK. The KRAS oncogene is mutated in roughly 45% of colorectal cancer. No targeted therapies currently in development have shown any activity in KRAS mutant CRC and finding novel approaches is a high priority. Such patients have a major unmet clinical need. In resectable CRC, the presence of KRAS mutation carries a minor adverse prognostic impact, but our recent studies have shown that in nearly 50% of patients whose tumours carry KRAS mutation, heightened IL-22 signaling is strongly associated with poor prognosis. This proposed experimental medicine study provides the next logical step in the clinical translation of this knowledge by exploring the effects of directly modulating IL-22 signaling in newly diagnosed CRC patients.

Data from this study with benefit a range of stakeholders, most importantly KRAS mutant CRC patients (a new therapeutic strategy for which there are currently no efficacious targeted therapies, with a clear pathway to efficacy testing through FOCUS-4 in stage IV patients); clinicians and the National Health Service (NHS) (through guidelines for patient stratification and improved resource uiltisation); Pharma/Biotech companies (through commercialisation of a biomarker test for IL22R expression and repurposing of existing assets licensed for inflammatory diseases in cancer); the UK economy broadly, and researchers (through greater understanding of synergies between cytokine signaling and oncogenic drivers in CRC and other cancers).

Results of this study will provide useful knowledge regarding the effects of IL-22 in human CRC and the precise molecular subtypes in which IL-22 blockade is most efficacious. This will provide a rationale from which to design and deploy anti-IL-22 trials with efficacy endpoints. The FOCUS4-C arm of the multi-site molecularly stratified FOCUS-4 colorectal cancer trial lead by Prof Tim Maughan will recruit KRAS mutant patients and represents a clear pathway to efficacy testing of anti-IL-22 therapy in stage IV patients. The results of these studies will define new guidelines for stratification of patients with KRAS mutant CRC and allow clinicians to stratify patients to targeted therapy based not only upon a genetic signature, but the unique integration of a genetic and immune signature.

The immune system is a double edge sword in cancer with beneficial anti-tumour immunity on one side and tumour-promoting inflammation on the other. Much excitement in the clinical and pharmaceutical spheres has emerged in recent years with the success of immune checkpoint blockade in some cancers. Combinatorial therapies harnessing anti-tumour immunity are an area of ongoing basic and clinical research. However, checkpoint blockade has shown minimal efficacy in colorectal cancer and only patients with microsatellite unstable tumours show any response. Preclinical studies from our lab and others support a strong pro-tumourigenic role for Th17-derived cytokines in CRC. This study will serve as an important proof of concept around targeting pro-tumourigenic cytokine signaling in the context of certain oncogenic mutations in cancer and allow for repurposing of existing assets licensed for inflammatory diseases in cancer. Furthermore, the commercialisation of a standardised immunohistochemical/gene expression based biomarker assay for measurement and patient stratification based on IL22R expression will foster academic/industrial partnerships leading to IP generation and wider economic benefit to the UK.

Finally, the novel synergy between cytokine signaling and an oncogenic driver is not unique to colorectal cancer. The biological understanding gleaned from this work will provide a launching point for further translational research for KRAS-IL-22 synergies in other cancers (ie. pancreatic cancer where KRAS mutation prevalence is 95%) and to explore other cytokine synergies with other oncogenic drivers.