Review of potential medical treatments for middle ear cholesteatoma

Abstract

Middle ear cholesteatoma (MEC), is a destructive, and locally invasive lesion in the middle ear driven by inflammation with an annual incidence of 10 per 100,000. Surgical extraction/excision remains the only treatment strategy available and recurrence is high (up to 40%), therefore developing the first pharmaceutical treatments for MEC is desperately required. This review was targeted at connecting the dysregulated inflammatory network of MEC to pathogenesis and identification of pharmaceutical targets. We summarized the numerous basic research endeavors undertaken over the last 30+ years to identify the key targets in the dysregulated inflammatory pathways and judged the level of evidence for a given target if it was generated by in vitro, in vivo or clinical experiments. MEC pathogenesis was found to be connected to cytokines characteristic for Th1, Th17 and M1 cells. In addition, we found that the inflammation created damage associated molecular patterns (DAMPs), which further promoted inflammation. Similar positive feedback loops have already been described for other Th1/Th17 driven inflammatory diseases (arthritis, Crohn's disease or multiple sclerosis). A wide-ranging search for molecular targeted therapies (MTT) led to the discovery of over a hundred clinically approved drugs already applied in precision medicine. Based on exclusion criteria designed to enable fast translation as well as efficacy, we condensed the numerous MTTs down to 13 top drugs. The review should serve as groundwork for the primary goal, which is to provide potential pharmaceutical therapies to MEC patients for the first time in history. Video Abstract.

Keywords: Adaptive immune response; Cholesteatoma; Chronic inflammation; Innate immune system; Positive feedback loops; Precision medicine.

Fig. 1

The proinflammatory intra and extracellular signalling in MEC disease. The orange background symbolizes the MEC, red represents the cytoplasm of residing cells and brown their nucleus. The level of evidence linking the depicted part of the pathway to MEC parthenogenesis are color-coded (red, yellow and green), proinflammatory deregulation is shown in blue. Fractions which were not investigated so far but bound to be a vital part of the proinflammatory signalling in MEC are shown in white. The pharmaceutical treatment options accessible within the inclusion criteria chosen in this review are shown as blue/red pills

Fig. 2

Regulation of Immune cell response in MEC. The colour coding is the same as in Fig. 1. Highlighted in red are the spirals of doom circles amplifying and exacerbating the already heightened inflammatory situation in MEC

Fig. 3

Osteolytic signalling network in MEC. The colour coding is the same as in Fig. 1. The two spirals of doom (red arrows) are interconnected at the generation of exogenous DAMPs derived from ECM tissue destruction

Fig. 4

The signalling leading to epidermal proliferation and angiogenesis. The colour coding is the same as in Fig. 1. The spiral of doom involving the increased epidermal proliferation is shown in red and revolves around endogenous DAMP generated from dying epithelial cells

Fig. 5

Flow chart of the method used to narrow down possible drugs applicable in a MTT approach for precision medicine for MEC