LAUSR

The National Cancer Institute defines mucositis as a complication of some cancer therapies characterised by inflammation of the mucosal surfaces of the digestive system, often seen as sores in the mouth. This is similar to the definition introduced in 2006 by the National Centre for Biotechnology Information (NCBI), which includes atrophy of the squamous epithelium and vascular damage in addition to inflammation. The science underpinning these definitions has involved decades of clinical and preclinical research by investigators perplexed by the challenges faced to adequately predict, prevent, and manage this complication. This editorial aims to present a snapshot of some major milestone work that has moved our understanding forward and highlight where this has created promising new approaches to reducing the burden of mucositis. Our initial understanding of mucositis was that it was caused by the non-specific actions of chemotherapy and radiation on susceptible epithelium, leading to cell death which was followed by inflammation due to breaches in epithelial integrity [1]. There has been evolving appreciation of the more complex and subtle nuances of the progression of injury leading to different presentations, as well as the development of “mucositis-like lesions” in response to the newer molecularly targeted and immune-based therapies [2]. As such, research now focuses on more than the absorptive epithelial lineage, but also immune and microbial contributions, the crypt niche supporting cells such as fibroblasts and secretory cells, and even neuroendocrine factors acting on enteric and autonomic nervous tissue [3]. The advent of technology that has enabled researchers to isolate specific pathways critical for mucositis development is arguably one of the most important developments in recent times. Through a reductionist approach, this has included the use of genetically modified organisms, particularly rodent models, to uncover targetable signals and molecular drivers. Examples include toll-like receptor (TLR) pathway knockout models of mucositis, which have shown that although TLRs are key contributors, regulating the communication between the host’s immune system and microbial ligands to dictate inflammatory responses [4]. Importantly, they have receptor and context-specific actions, with deletion of TLR4, TLR2, TLR9, and the downstream adaptor protein MYD88 protecting against irinotecan-induced mucositis [5, 6]. Whereas TLR2 knockout exacerbates methotrexate-induced intestinal mucositis, although this is rescued when the adapter protein MD-2 is also deleted [7]. Augmenting these pathways in a translationally meaningful manner has proved challenging. As such, intelligent design of therapeutics to intervene in these pathways is required and may be suited to targets further down the pathway, including inflammatory mediators such as NF-κB, which appear more ubiquitously associated with injury. Work using transgenic mice expressing nuclear protein Smad7 in keratinocytes has shown that antagonizing NF-κB effectively prevents radiotherapy-induced oral mucositis [8]. Furthermore, Smad7 delivered as a local therapy also prevented oral mucositis in mice and dogs, and was able to significantly reduce epithelial apoptosis [9, 10], indicating improved translatability of this approach. Another wellcharacterised mediator of NF-κB is oxidative stress mediated by reactive oxygen and nitrogen species, with oxygen radical scavengers and antioxidant enzymes showing promise against mucositis [11, 12]. One such agent, avasopasen manganese (GC4419), a superoxide dismutase mimetic, has shown promise in a large phase IIb clinical trial to reduce the incidence, duration, and severity of oral mucositis in patients with head and neck cancer treated with radiotherapy [13]. The confirmatory phase III trial (ROMAN; ClinicalTrials.gov identifier: NCT03689712) is currently underway with results expected in 2023, showing a clear example of how the science of mucositis can be translated to clinical therapeutics. Another significant leap forward is the use of personalised medicine, revolutionised in main-stream cancer biology, in * Joanne Bowen [email protected]