In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part III.

The development of in vitro/in vivo translational methods and a clinical trial framework for synergistically acting drug combinations are needed to identify optimal therapeutic conditions with the most effective therapeutic strategies. We performed physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) modelling and virtual clinical trial simulations for siremadlin, trametinib, and their combination in a virtual representation of melanoma patients. In this study, we built PBPK/PD models based on data from in vitro absorption, distribution, metabolism, and excretion (ADME), and in vivo animals' pharmacokinetic-pharmacodynamic (PK/PD) and clinical data determined from the literature or estimated by the Simcyp simulator (version V21). The developed PBPK/PD models account for interactions between siremadlin and trametinib at the PK and PD levels. Interaction at the PK level was predicted at the absorption level based on findings from animal studies, whereas PD interaction was based on the in vitro cytotoxicity results. This approach, combined with virtual clinical trials, allowed for the estimation of PK/PD profiles, as well as melanoma patient characteristics in which this therapy may be noninferior to the dabrafenib and trametinib drug combination. PBPK/PD modelling, combined with virtual clinical trial simulation, can be a powerful tool that allows for proper estimation of the clinical effect of the above-mentioned anticancer drug combination based on the results of in vitro studies. This approach based on in vitro/in vivo extrapolation may help in the design of potential clinical trials using siremadlin and trametinib and provide a rationale for their use in patients with melanoma.

In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part I.

Translation of the synergy between the Siremadlin (MDM2 inhibitor) and Trametinib (MEK inhibitor) combination observed in vitro into in vivo synergistic efficacy in melanoma requires estimation of the interaction between these molecules at the pharmacokinetic (PK) and pharmacodynamic (PD) levels. The cytotoxicity of the Siremadlin and Trametinib combination was evaluated in vitro in melanoma A375 cells with MTS and RealTime-Glo assays. Analysis of the drug combination matrix was performed using Synergy and Synergyfinder packages. Calculated drug interaction metrics showed high synergy between Siremadlin and Trametinib: 23.12%, or a 7.48% increase of combined drug efficacy (concentration-independent parameter ß from Synergy package analysis and concentration-dependent δ parameter from Synergyfinder analysis, respectively). In order to select the optimal PD interaction parameter which may translate observed in vitro synergy metrics into the in vivo setting, further PK/PD studies on cancer xenograft animal models coupled with PBPK/PD modelling are needed.

In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part II.

The development of in vitro/in vivo translational methods for synergistically acting drug combinations is needed to identify the most effective therapeutic strategies. We performed PBPK/PD modelling for siremadlin, trametinib, and their combination at various dose levels and dosing schedules in an A375 xenografted mouse model (melanoma cells). In this study, we built models based on in vitro ADME and in vivo PK/PD data determined from the literature or estimated by the Simcyp Animal simulator (V21). The developed PBPK/PD models allowed us to account for the interactions between siremadlin and trametinib at PK and PD levels. The interaction at the PK level was described by an interplay between absorption and tumour disposition levels, whereas the PD interaction was based on the in vitro results. This approach allowed us to reasonably estimate the most synergistic and efficacious dosing schedules and dose levels for combinations of siremadlin and trametinib in mice. PBPK/PD modelling is a powerful tool that allows researchers to properly estimate the in vivo efficacy of the anticancer drug combination based on the results of in vitro studies. Such an approach based on in vitro and in vivo extrapolation may help researchers determine the most efficacious dosing strategies and will allow for the extrapolation of animal PBPK/PD models into clinical settings.

Morphology, phylogeny, and molecular dating in Plagiogrammaceae family focused on Plagiogramma-Dimeregramma complex (Urneidophycidae, Bacillariophyceae).

Although previous phylogenetic analyses suggested that the araphid diatom family Plagiogrammaceae is monophyletic, there is still not a clear understanding of relationships among the genera, and the taxonomy of several genera--Dimeregramma and Plagiogramma--remains questionable in light of paraphyly for both genera using molecular and morphological data. We have expanded the available DNA for molecular work for dozens of plagiogrammacean clones and analyzed 29 morphological characters from plagiogrammarian taxa and closely related genera, to increase understanding of the evolutionary history and systematics of the family and re-evaluate the current taxonomical classification of plagiogrammacean genera. The addition of more taxa and more data confirm the results from previous molecular phylogenies: most plagiogrammacean genera are monophyletic, except for Dimeregramma and Plagiogramma. Interestingly, the morphological analysis resolves only Talaroneis and Glyphodesmis as monophyletic. Given these results, we feel there is limited support for retaining Dimeregramma and Plagiogramma as distinct genera, and formally propose amending Plagiogramma and transferring six Dimeregramma species. As the Plagiogrammaceae is also one of the first-diverging clades of pennate diatoms, we also used these molecular data to estimate the age of the family, based on multiple calibration points derived from fossil taxa within or close to the Plagiogrammaceae. The results indicated that the Plagiogrammaceae evolved more than 114 million year ago and its diversification appears to correspond to a time of climate cooling. Additionally, we described a new monotypic genus (Coccinelloidea) with one new species C. gracilis, and five new species within established genera, e.g. Plagiogramma marginalis, Plagiogramma harenae, Plagiogramma porcipellis, Neofragilaria montgomeryii and Psammogramma anacarae.

MDM2-p53 Interaction Inhibitors: The Current State-of-Art and Updated Patent Review (2010-Present).

BACKGROUND: Mouse Double Minute 2 protein (MDM2) is a cellular regulator of p53 tumor suppressor (p53). Inhibition of the interaction between MDM2 and p53 proteins is a promising anticancer therapy. OBJECTIVE: This updated patent review is an attempt to compile the research and achievements of the various researchers working on small molecule MDM2 inhibitors from 2010 to date. We provide an outlook into the future for therapy based on MDM2 inhibition by presenting an overview of the most relevant patents which have recently appeared in the literature. METHODS: Literature and recent patents focusing on the anticancer potential of MDM2-p53 interaction inhibitors and its applications have been analyzed. We put the main emphasis on the most perspective compounds which are or were examined in clinical trials. RESULTS: Literature data indicated that MDM2 inhibitors are therapeutically effective in specific types of cancer or non-cancer diseases. A great number of patents and research work around new MDM2- p53 interaction inhibitors, possible combinations, new indications, clinical regimens in previous years prove that this targeted therapy is in the scope of interest for many business and academic research groups. CONCLUSION: Novel MDM2 inhibitors thanks to higher potency and better ADME properties have shown effectiveness in preclinical and clinical development however the final improvement of therapeutic potential for MDM2 inhibitors might depend on the useful combination therapy and exploring new cancer and non-cancer indications.

Life in a temperate Polar sea: a unique taphonomic window on the structure of a Late Cretaceous Arctic marine ecosystem.

As the earth faces a warming climate, the rock record reminds us that comparable climatic scenarios have occurred before. In the Late Cretaceous, Arctic marine organisms were not subject to frigid temperatures but still contended with seasonal extremes in photoperiod. Here, we describe an unusual fossil assemblage from Devon Island, Arctic Canada, that offers a snapshot of a ca 75 Myr ago marine palaeoecosystem adapted to such conditions. Thick siliceous biogenic sediments and glaucony sands reveal remarkably persistent high primary productivity along a high-latitude Late Cretaceous coastline. Abundant fossil faeces demonstrate that this planktonic bounty supported benthic invertebrates and large, possibly seasonal, vertebrates in short food chains. These ancient organisms filled trophic roles comparable to those of extant Arctic species, but there were fundamental differences in resource dynamics. Whereas most of the modern Arctic is oligotrophic and structured by resources from melting sea ice, we suggest that forested terrestrial landscapes helped support the ancient marine community through high levels of terrigenous organic input.