1.Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma.
Bassiri H1, Benavides A1, Haber M1, Gilmour SK1, Norris MD1, Hogarty MD1. Transl Pediatr. 2015 Jul;4(3):226-38. doi: 10.3978/j.issn.2224-4336.2015.04.06.
Neuroblastoma is a childhood tumor in which MYC oncogenes are commonly activated to drive tumor progression. Survival for children with high-risk neuroblastoma remains poor despite treatment that incorporates high-dose chemotherapy, stem cell support, surgery, radiation therapy and immunotherapy. More effective and less toxic treatments are sought and one approach under clinical development involves re-purposing the anti-protozoan drug difluoromethylornithine (DFMO; Eflornithine) as a neuroblastoma therapeutic. DFMO is an irreversible inhibitor of ornithine decarboxylase (Odc), a MYC target gene, bona fide oncogene, and the rate-limiting enzyme in polyamine synthesis. DFMO is approved for the treatment of Trypanosoma brucei gambiense encephalitis ("African sleeping sickness") since polyamines are essential for the proliferation of these protozoa. However, polyamines are also critical for mammalian cell proliferation and the finding that MYC coordinately regulates all aspects of polyamine metabolism suggests polyamines may be required to support cancer promotion by MYC.
2.Input estimation for drug discovery using optimal control and Markov chain Monte Carlo approaches.
Trägårdh M1,2, Chappell MJ3, Ahnmark A4, Lindén D4, Evans ND3, Gennemark P5. J Pharmacokinet Pharmacodyn. 2016 Apr;43(2):207-21. doi: 10.1007/s10928-016-9467-z. Epub 2016 Mar 1.
Input estimation is employed in cases where it is desirable to recover the form of an input function which cannot be directly observed and for which there is no model for the generating process. In pharmacokinetic and pharmacodynamic modelling, input estimation in linear systems (deconvolution) is well established, while the nonlinear case is largely unexplored. In this paper, a rigorous definition of the input-estimation problem is given, and the choices involved in terms of modelling assumptions and estimation algorithms are discussed. In particular, the paper covers Maximum a Posteriori estimates using techniques from optimal control theory, and full Bayesian estimation using Markov Chain Monte Carlo (MCMC) approaches. These techniques are implemented using the optimisation software CasADi, and applied to two example problems: one where the oral absorption rate and bioavailability of the drug eflornithine are estimated using pharmacokinetic data from rats, and one where energy intake is estimated from body-mass measurements of mice exposed to monoclonal antibodies targeting the fibroblast growth factor receptor (FGFR) 1c.
3.Quilamine HQ1-44, an iron chelator vectorized toward tumor cells by the polyamine transport system, inhibits HCT116 tumor growth without adverse effect.
Renaud S1, Corcé V2, Cannie I3, Ropert M4, Lepage S5, Loréal O3, Deniaud D6, Gaboriau F7. Biochem Pharmacol. 2015 Aug 1;96(3):179-89. doi: 10.1016/j.bcp.2015.06.001. Epub 2015 Jun 10.
Tumor cell growth requires large iron quantities and the deprivation of this metal induced by synthetic metal chelators is therefore an attractive method for limiting the cancer cell proliferation. The antiproliferative effect of the Quilamine HQ1-44, a new iron chelator vectorized toward tumor cells by a polyamine chain, is related to its high selectivity for the Polyamine Transport System (PTS), allowing its preferential uptake by tumoral cells. The difference in PTS activation between healthy cells and tumor cells enables tumor cells to be targeted, whereas the strong dependence of these cells on iron ensures a secondary targeting. Here, we demonstrated in vitro that HQ1-44 inhibits DNA synthesis and cell proliferation of HCT116 cells by modulating the intracellular metabolism of both iron and polyamines. Moreover, in vivo, in xenografted athymic nude mice, we found that HQ1-44 was as effective as cis-platin in reducing HCT116 tumor growth, without its side effects.
4.Suppression of ornithine decarboxylase promotes osteogenic differentiation of human bone marrow-derived mesenchymal stem cells.
Tsai YH1, Lin KL1, Huang YP2, Hsu YC3, Chen CH4, Chen Y5, Sie MH1, Wang GJ6, Lee MJ7. FEBS Lett. 2015 Jul 22;589(16):2058-65. doi: 10.1016/j.febslet.2015.06.023. Epub 2015 Jun 30.
Ornithine decarboxylase (ODC) is the rate-limiting enzyme for polyamine biosynthesis. Suppression of ODC by its irreversible inhibitor, α-difluoromethylornithine (DFMO), or by RNA interference through siRNA, enhanced osteogenic gene expression and alkaline phosphatase activity, and accelerated matrix mineralization of human bone marrow-derived mesenchymal stem cells (hBMSCs). Besides, adipogenic gene expression and lipid accumulation was attenuated, indicating that the enhanced osteogenesis was accompanied by down-regulation of adipogenesis when ODC was suppressed. A decrease in the intracellular polyamine content of hBMSCs during osteogenic induction was observed, suggesting that the level of endogenous polyamines is regulated during differentiation of hBMSCs. This study elucidates the role of polyamine metabolism in the lineage commitment of stem cells and provides a potential new indication for DFMO as bone-stimulating drug.
