New cancer therapy by targeting tumor metabolism

Cancer cells are known to be sugar-loving cells i.e. they consume a lot of sugar in order to survive. This discovery was made already in 1924 by the German scientist Otto Warburg has not been recognized as important for the development of cancer. I the last 10 years however, Warburgs ideas has been brought back into attention and the metabolic switch into sugar-loving cells now carries the name after its discoverer namely the Warburg effect. The Warburg effect is now considered not only a byproduct of cancer but one of the seven hallmarks of the initiation and development of cancer. Arctic Pharma has developed potent inhibitors of cancer cells glycolysis, that is their ability to metabolize sugar as a source of carbon building blocks and energy. In this way we target the biological basis for cancer growth: the reduces need for energy and a tremendous need for biological building blocks needed in the form of protein, lipids and DNA in order to divide into two daughter cells. In this project, Arctic Pharma has improved our potent inhibitors of cancer cell line growth, both regarding dosage and side effects. This was achieved by medicinal chemistry and constant testing of the newly synthesized compounds for dose, side effects and toxicity. Chemical changes that improved in one or more features were taken further and combined with other positive changes, while worse-performing compounds was discarded. After several iterative cycles of synthesis and testing, we are now close to proof-of-concept studies in mice.

Worldwide, about 15 million cancers are annually diagnosed and about 8 million people die from cancer each year, making cancer a top-three cause of death in the world. Arctic Pharma's underlying idea is to develop a drug that kills cancer cells by attacki ng the core of their metabolism. The Warburg effect, recognized as a switch to glycolysis-dependent metabolism by cancer cells, has recently been revitalized as a requirement for the development of cancer, equivalent to activation of proto-oncogenes and l oss of tumor suppressor effects. In the search for a novel cancer therapy, Arctic Pharma has chosen to target lactate dehydrogenase (LDH), a key player of the Warburg effect. The main objective of this project is to optimize our highly potent inhibitors o f cancer cell growth into advanced hits and identify a PDX model. The main research challenge in the project is to improve efficacy and selectivity of our compound series, and at the same time maintain desired physio-chemical properties and a good toxicol ogy profile. The research will comprise SAR expansion, medicinal chemistry and patient-derived xenograft mouse models. Developmental work performed this far in Arctic Pharma's laboratories indicates that the novel drug works against a variety of cancer ty pes tested. In the initial pipeline, we will focus on breast cancer, as for instance the Luminal A subtype of breast cancer has shown an increased Warburg effect. Arctic Pharma will actively seek to document and patent the results from this project. The p atents will be key value creation and the basis for partnership, funding and further drug development along the value chain towards an approved drug on the mark