Optimization of novel microbially produced compounds with anti-cancer activity

SINTEF has through screening and characterization of marine microorganisms identified a bacterium producing a compound with a potent effect against cancer cell cultures. Results also indicate that the compound has a novel mode of action, making it a good candidate for use in combination therapy to improve overall effect of the medicine. Through this project, SINTEF has developed the bacteria and production process to produce new analogues of the compound, with improved effect, solubility and bioavailability - properties essential to use the compound as a medicine. The three most promising new analogues have been produced and characterized, and subjected to extended screening of effect against a broad set of cell lines and in animal studies, to evaluate if the new compounds have what it takes to proceed into clinical application.

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.