The oral mucosa is a stratified squamous epithelium that has a crucial barrier function. Any damage or loss of integrity during oncology therapies poses a major risk of infection, since such patients are often also immunocompromized. Furthermore, the large ulcerations can be so painful that patients are often unable to eat and require hospitalization and enteral nutrition. These side effects can therefore often be dose, and hence cure, limiting and incur significant healthcare costs. Hence, there is a high demand for mucositis therapies.
Treatments currently available are mainly designed to act as artificial barriers or combat infections, in addition to providing pain relief. The only marketed prophylactic treatment to prevent or reduce ulceration is Kepivance/Palifermin (Keratinocyte Growth Factor), first launched in 2004. Despite many preclinical studies evaluating new therapies since then, and deeming them effective, to date no others have successfully progressed through clinical trials and been licenced for use. This clearly therefore questions the utility of the selected preclinical models. Is too much preclinical good news a reflection of the poor choice or use of the models?
Preclinical models of oral mucositis have been dominated by those using the Syrian hamster cheek pouch. Epistem and others (notably Dorr et al) have preferred the lesser used mouse model. Both have pros and cons.
The mouse tongue model has several advantages:
One can compare the responses of an identical tongue region in each mouse and thereby reduce variability due to the keratinization patterns or cell turnover differences present in slightly different regions, especially in the buccal mucosa/pouch.
The use of a histological objective analysis, rather than a subjective visual score, whilst more expensive, further reduces variability and improves data accuracy.
The mouse model is also more humane as histological readouts tracking the extent of epithelial thinning and onset/speed of regeneration meaning that there is no need to proceed to overt ulceration.
One often overlooked advantage of the mouse model is that known PK data can be cross applied, along with PD data from other mouse models. For example, mouse xenografts are often used to demonstrate that any mucositis treatment does not pose a safety risk (by protecting a tumor or promoting tumor growth).
When mechanism of action (MOA) analyses are undertaken there are also more readily available antibodies and primers.
Conversely, with the hamster model:
By using serial visual reviews of the same animals, it is cheaper and quicker to run as a model (explaining its popularity).
The scores are compatible with the WHO human evaluation system.
By progressing to full ulceration it is also suitable for evaluating effects on large ulcer wound healing and pain reduction.
It may be stating the obvious, but investigators should choose the most suitable model based on the MOA of their drug, and in some cases run both the mouse and hamster models. In either case the timing of drug administration is pivotal to efficacy outcome – not simply from a PK/MOA perspective but also from that of both the oral circadian rhythm and the most responsive stage of the ulceration process. Inappropriate scheduling is very often the explanation for a negative result (in mouse and man).