Anti-mitotic drugs that inhibit microtubule dynamics have been effective in the treatment of cancer. Despite their proven clinical success, their effectiveness is limited by two critical aspects: resistance and toxicity (mainly myelosuppression and neuropathies). In efforts to avoid adverse side effects, small molecule inhibitors were developed to target the critical regulators of mitosis, such as polo-like kinase 1 (Plk1). The validation of Plk1 as a drug target led to the rapid pharmaceutical development and clinical evaluation of a growing number of Plk inhibitors. Recently Plk1 inhibitors entered the clinic. However, a major concern in targeting Plk1 for cancer therapy still is the potential toxicity in normal tissues due to the pleiotropic functions in mitosis.
Monika Raab and her collegues used an RNA interference (RNAi) approach to be able to silence the expression of Plk1 in adult animals, thus reflecting a clinical situation of cancer drug therapy. Plk1 silencing reached between 60% and 86% in different organs.
The transgene Plk1-iKD (inducible knock down) mice were analysed in the German Mouse Clinic to investigate the influence of Plk1 silencing on the phenotype of the mice.
The morphological screening did not reveal differences between treated and control mice. A mild inhibition of the proliferative activity was observed in ovarian follicles and the mucosal folds of the large intestine. The GMC metabolic screening programme provided a comparative analysis of bioenergetic parameters in the transgenic mice. The mechanisms that lead to disturbances in body weight regulation and energy metabolism were examined, including food consumption, energy uptake, faeces production, energy content in the faeces and metabolized energy, which all remained unchanged. Despite their low values of assimilated energy, male Plk1-iKD mice had a significantly increased body mass and rectal temperature compared with those of control animals. A significant induction of apoptosis was not apparent in murine tissues. Since the counterpart of Plk1 in Drosophila, polo, is known to be crucial for normal spermatogenesis, testes of Plk1-iKD mice were analysed but no pathological phenotype was identified.
Hence, this study suggests the existence of a therapeutic window for monospecific Plk1 inhibitors to kill tumour cells while sparing normal cells. This differential addiction of normal and cancer cells to Plk1 may also provide the rationale for using Plk1-monospecific drugs for chemoprevention in individuals with a hereditary cancer background (for example, breast, colon and prostate) or in other patients with premalignant lesions such as ductal carcinoma in situ DCIS.
Furthermore this study shows that genetically engineered mouse models (GEMMs) can faithfully reflect many of the fundamental traits of human cancer. Thus they are valuable tools for understanding the biology of tumour development and growth.
Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells, Raab et al., naturecommunications | 2:395 | DOI: 10.1038/ncomms1395