MEMBRANELIPIDTHERAPY · Membrane lipid composition as new antitumor therapeutic target: sphingomyelin synthase (SGMS) at the basis of Minerval® mechanism of action and design of new Minerval®-related drugs

MembraneLipidTherapy proposal is a translational research project introducing an innovative therapeutic approach for fighting cancer disease that takes advantage of inter-sectoral industry-academia strengths and international cooperation.Membrane Lipid Therapy relies on the specific lipid composition from the cell membrane in tumour cells as a strong element controlling tumour growth surpassing oncogene activation or tumour suppressor inactivation. Particularly the ratio of membrane lipids phosphatidilethanol-amine:sphingomyelin (PE:SM) is ten times higher in tumour cells when compared to wild type cells.This finding allowed the host group to rationally design the new antitumor drug Minerval®, first known activator of sphingomyelin synthase (SGMS-1 and -2), the protein responsible for maintaining the balance between PE and SM in the membrane by using the former as substrate to synthesize the latter. Minerval®, developed by Lipopharma Therapeutics (spin-off company from University of the Balearic Islands), is currently in multicenter phase II clinical trial for treatment of gliomas and other solid tumours.All of the above supports Minerval® relevance as new antitumor therapy; however, further characterization of the molecular mechanism underlying Minerval® action is needed for approval and distribution of Minerval in the next future. The aim of this project is to gain more insight in this issue.Laboratory animal models combined with histology techniques, microscopy and imaging and molecular biology techniques together with analytical chemistry, molecule structure techniques and computer-aided drug design will be used to determine:1. The molecular mechanism underlying the altered PE:SM ratio in tumour cells.2. The domains in SGMS interacting with Minerval.3. The molecular pathway implicated in SGMS regulation.Last but not least, the generated knowledge will be used for the ultimate aim of designing new drugs targeting SGMS1 and SGMS2 for antitumor therapy.