Thalidomides teratogenicity has been a subject of much debate and over the years numerous hypotheses have been proposed. Two of the best-known have been the anti-angiogenesis hypothesis and oxidative stress model hypothesis, with considerable experimental evidence supporting these two hypotheses regarding thalidomides teratogenicity.
Recently, new findings have emerged that suggest a novel mechanism of teratogenicity. Cereblon is a 51 kDa protein localized in the cytoplasm, nucleus and peripheral membrane of cells in numerous parts of the body. It acts as a component of the E3 ubiquitin ligase, regulating various developmental processes, including embryogenesis, carcinogenesis and cell cycle regulation, through degradation (ubiquitination) of unknown substrates. Thalidomide has been shown to bind to cereblon, inhibiting the activity of the E3 ubiquitin ligase, resulting in accumulation of the ligase substrates and downregulation of fibroblast growth factor 8 (FGF8) and FGF10. This disrupts the positive feedback loop between the two growth factors, possibly causing both multiple birth defects and anti-myeloma effects.
Findings also support the hypothesis that an increase in the expression of cereblon is an essential element of the anti-myeloma effect of both lenalidomide and pomalidomide. Cereblon expression was three times higher in responding patients compared to non-responders and higher cereblon expression was also associated with partial or full response while lower expression was associated with stable or progressive disease.