Mathematical modelling of clonal reduction therapeutic strategies in acute myeloid leukemia.

Over the years, the overall survival of older patients diagnosed with acute myeloid leukemia (AML) has not significantly increased. Although standard cytotoxic therapies that rapidly eliminate dividing myeloblasts are used to induce remission, relapse can occur due to surviving therapy-resistant leukemic stem cells (LSCs). Hence, anti-LSC strategies have become a key target to cure AML. We have recently shown that previously approved cardiac glycosides and glucocorticoids target LSC-enriched CD34+ cells in the primary human AML 8227 model with more efficacy than normal hematopoietic stem cells (HSCs). To translate these in vitro findings into humans, we developed a mathematical model of stem cell dynamics that describes the stochastic evolution of LSCs in AML post-standard-of-care. To this, we integrated population pharmacokinetic-pharmacodynamic (PKPD) models to investigate the clonal reduction potential of several promising candidate drugs in comparison to cytarabine, which is commonly used in high doses for consolidation therapy in AML patients. Our results suggest that cardiac glycosides (proscillaridin A, digoxin and ouabain) and glucocorticoids (budesonide and mometasone) reduce the expansion of LSCs through a decrease in their viability. While our model predicts that effective doses of cardiac glycosides are potentially too toxic to use in patients, simulations show the possibility of mometasone to prevent relapse through the glucocorticoid's ability to drastically reduce LSC population size. This work therefore highlights the prospect of these treatments for anti-LSC strategies and underlines the use of quantitative approaches to preclinical drug translation in AML.

Ovariectomy reduces cholinergic modulation of excitatory synaptic transmission in the rat entorhinal cortex.

Estrogens are thought to contribute to cognitive function in part by promoting the function of basal forebrain cholinergic neurons that project to the hippocampus and cortical regions including the entorhinal cortex. Reductions in estrogens may alter cognition by reducing the function of cholinergic inputs to both the hippocampus and entorhinal cortex. In the present study, we assessed the effects of ovariectomy on proteins associated with cholinergic synapses in the entorhinal cortex. Ovariectomy was conducted at PD63, and tissue was obtained on PD84 to 89 to quantify changes in the degradative enzyme acetylcholinesterase, the vesicular acetylcholine transporter, and muscarinic M1 receptor protein. Although the vesicular acetylcholine transporter was unaffected, ovariectomy reduced both acetylcholinesterase and M1 receptor protein, and these reductions were prevented by chronic replacement of 17ß-estradiol following ovariectomy. We also assessed the effects of ovariectomy on the cholinergic modulation of excitatory transmission, by comparing the effects of the acetylcholinesterase inhibitor eserine on evoked excitatory synaptic field potentials in brain slices obtained from intact rats, and from ovariectomized rats with or without 17ß-estradiol replacement. Eserine is known to prolong the effects of endogenously released acetylcholine, resulting in an M1-like mediated reduction of glutamate release at excitatory synapses. The reduction in excitatory synaptic potentials in layer II of the entorhinal cortex induced by 15-min application of 10 µM eserine was greatly reduced in slices from ovariectomized rats as compared to intact rats and ovariectomized rats with replacement of 17ß-estradiol. The reduced modulatory effect of eserine is consistent with the observed changes in cholinergic proteins, and suggests that reductions in 17ß-estradiol following ovariectomy lead to impaired cholinergic function within the entorhinal cortex.