Optimization of novel microbially produced compounds with anti-cancer activity

SINTEF har gjennom karakterisering av marine mikroorganismer identifisert en bakterie som produserer et stoff med svært god effekt mot dyrkede kreftcellelinjer. Resultater tyder på at stoffet kan ha en spesiell virkningsmekanisme, som gjør stoffet til en god kandidat å bruke sammen med andre typer cellegift for å forbedre effekt av kreftbehandlingen. Gjennom dette prosjektet har SINTEF utviklet bakterien og produksjonsprosessen for å produsere nye varianter av stoffet med forbedret effekt, løselighet og biotilgjengelighet - egenskaper som er viktige for å kunne bruke stoffet som medisin. De tre mest lovende nye variantene av stoffet er produsert og karakterisert, før de blir sendt til utvidet screening av effekt i cellekultur og dyrestudier, for å vurdere om de nye stoffene har det som trengs for å gå videre mot medisinsk anvendelse.

SINTEF holds a key patent for a microbial antibiotic that is highly cytotoxic to cultured cancer cell lines, including cell lines that are resistant to current chemotherapeutics. There is evidence that this compound acts through novel mechanisms, and it may therefore act synergistically with other cancer drugs. By genetic modification of the producer bacterium (streptomyces sp.) SINTEF has generated structural compound variants that retain biological activity while likely exhibiting improved pharmacological properties, such as higher solubility. This project aims to further optimize such variants and their production system toward a potential anticancer drug candidate. SINTEF has a unique capability in Norway for rapidly evaluating multiple compounds against a large number of relevant cell lines through high capacity screening and robotics. Evaluation criteria during optimization include in vitro potency, selectivity (cancer cells vs healthy cells), physicochemical properties, and production yields. Preliminary fermentation studies indicate that satisfactory product yields may be obtained through process optimizations, such as of fermentation media. Potential drug leads emerging from the in vitro studies will advance to preliminary in vivo studies, assessing acute toxicity. Compounds demonstrating sufficient anticancer potential in vitro studies will be submitted to the Developmental Therapeutics Program at NCI for in vivo efficacy testing in relevant mouse models. The primary cancer target for this project is leukemia, with initial focus on acute myeloid leukemia (AML), which is a severe disease with high unmet medical needs. Because of the lack of effective marketed drugs, almost half of current AML patients are enrolled in clinical trials and treated with experimental drugs. This presents a unique opportunity for building commercial value from a SINTEF patent while addressing a critical medical need at the earliest possible stage.