Combining Radiation with JAK inhibitors as a novel therapeutic strategy for rectal cancer

Background In addition to the use of neoadjuvant radiotherapy (RT) little progress has been made over the past 20-years for treatment of locally advanced rectal cancer.

Novel RT-based combination therapies are highly sought after to improve treatment responses and expand organ preservation.

Our data demonstrates that in rectal cancer patient specimens IL6 expression and activation of the STAT3 pathway are associated with poor patient prognosis, RT also induces up-regulation of IL6 expression, and STAT3 activation and patient derived organoids (PDO) treated with JAK inhibitors +/- RT undergo cell death.

Taken together this supports inhibition of the IL6/JAK/STAT3 pathway as a therapeutic approach for rectal cancer.

However, the optimal scheduling of RT and JAK inhibitors is not yet clear, and the subgroups of patients that will gain most benefit from this therapeutic strategy is yet to be defined.

Aims We hypothesis that “RT via stimulation of IL6 production in the tumor microenvironment will sensitize rectal cancer to inhibition of the IL6/JAK/STAT3 cascade.” In order to test this hypothesis we will establish if up-regulation of IL6/JAK/STAT3 signaling in rectal cancer patient specimens is influenced by rectal cancer phenotype.

We will also establish what the optimal scheduling is for RT/JAK inhibition combination therapy and to what patients it should be administered. Methods We will utilize 2 patient rectal cancer cohorts, from both Glasgow and Oxford.

Using pre and post RT treatment biopsies, RNAScope and IHC will be employed to establish if IL6 expression and STAT3 activation increases in response to RT.

This will be combined with genomic, transcriptomic and histological data to establishing if RT increases IL6 resulting in STAT3 activation in all rectal tumors or those from one particular genetic background, consensus molecular subtype (CSM), histological subtype (GSM) and stem cell index.

Mouse and PDO models will be employed to establish the optimal combination therapy of RT and JAK 1/2 inhibitor Ruxilitinib or JAK2/3 inhibitor Tofacitinib at a range of concentrations plus and minus 5FU.

Again a range of genetic background, CSM, GSM or stem cell index will be used to determine if response to combination therapy is observed across all or a particular subtype of rectal cancer. How the results of this research will be used.

This project will harness expertise across 3 RadNet centres to provide evidence that repurposing of JAK inhibitors could be utilized in rectal cancer, identify predictive biomarkers and provide data for future grant applications .