Optimization of sulfalsalazine derivatives for cancer therapeutics
Prof. Per Enger, University of Bergen; Prof. Hans Bjørsvik, University of Bergen
Treatment failure is a grave concern to clinicians that have cancer patients in their care, and poses a considerable scientific challenge. The socieoeconomic burden this causes on the patient and their families are insurmountable. The aim described here is to innovate current radiation treatment by optimizing a pharmacological strategy to overcome radioresistance in cancer.
The main principle of this approach is to administer synthetic Sulfasalazine analogues during radiotherapy to increase oxidative stress. Previously we have shown that Sulfasalazine (SAS) act as a radiosensitiser in a brain tumor animal model by blocking the xCT antiport and thereby synthesis of Glutathione (GSH). This anti-oxidant constitutes a major defense system against reactive oxygen species in mammalian cells. Based on these findings, we have generated synthetic Sulfasalazine analogues with optimized properties regarding drug uptake, toxicity profile and biological efficacy (potency of xCT inhibition).
Our project makes use of state-of-the-art animal models with orthotopic xenografting of patient tumor biopsies that are highly representative of the human tumor in situ, compared to in vitro propagated cancer cell lines. We will first model the Glioblastoma Multiforme since we are experts in this area, and have shown that these analogues uniquely can increase GSH levels. Further, we believe that these derivatives may be marketed and extended to other cancer forms such as breast and lung cancer as well.
Our current data suggests that SAS sensitizes glioblastoma to radiation treatment. Thus, SAS administered over a short time period can potentiate the effect of Gamma Knife Radiosurgery (GKRS). Based on this result, we have obtained all necessary approvals (etikansökningsnämden og läkemedelsverket) for a clinical trial phase I.
We have engaged Dr. Philip Webber at Dehns in Oxford to counsel us on a patent strategy and we have submitted a patent. In its simplest terms, the invention relates to new chemical compounds (radiosensitisers) for use in a medical treatment (of cancer) that are new derivatives of styrylbenzoic acid (SBAs).
(Sleire et al. Oncogene 2015)