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  • Final Report Summary - 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.)

Final Report Summary - 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.)

The purpose of this project was to take advantage of membrane lipid composition as new antitumor therapeutic target: with a focus in sphingomyelin synthase (SGMS) at the basis of Minerval’s (2-hydroxyoleic acid, 2OHOA) mechanism of action and in designing new Minerval-related drugs. Initially scheduled to last 24 months, the project lasted only 17 months and a half, due to the resignation of the researcher when she was offered a new position.
Cell division in a healthy subject is precisely controlled by numerous mechanisms. Cancer arises when the cell division cycle is altered and defective cells multiply in an uncontrolled fashion. The current view of oncogenic transformation from a normal to cancer cell implies activation of an oncogene (that promotes proliferation and tumorogenesis) and inactivation of a tumour suppressor gene (that protects the cell from malignancy). Dr. Pablo V. Escribá group has developed a revolutionary antitumor therapeutic strategy called Membrane Lipid Therapy MLT (Escriba, 2006). This relies on the specific lipid composition from the cell membrane in tumour cells as a potent element upstream oncogene activation or tumour suppressor inactivation.

MembraneLipidTherapy project was a translational research project introducing an innovative therapeutic approach for fighting cancer that took advantage of inter-sectoral industry-academia strengths and international cooperation. This was also an interdisciplinary project in which lipid chemistry, bioinformatics/Computer-Aided Drug Design (CADD) and molecular biology meet to improve the treatment of several cancers.
Regarding mechanism of action of Minerval, it is the first known activator of sphingomyelin synthase (SGMS-1 and -2), the protein responsible for keeping the balance between phosphatidilethanolamine (PE) and sphingomyelin (SM) in the membrane by using the former as substrate to synthesize the latter. Minerval, which has been designated ‘orphan drug’ by the European Medicines Agency (EMA), has now finished a multicentre phase I/IIa clinical trial for the treatment of gliomas and other solid tumours. This project aimed to further characterise the molecular mechanisms underlying Minerval’s action for future marketing and for the design of new anticancer drugs. Actually, Minerval is stronger than the reference drug for the treatment of glioma temozolomide. Life expectancy in glioma patients is only increased around 10 weeks after temozolomide treatment because gliomas relapse due to drug resistance. However, no relapse has been observed after Minerval treatment in mouse models. This result is even more promising when considering that median life expectancy for glioma patients is 14 months (Stupp et al, 2005). In favour of this, EMA classified Minerval as orphan drug due to its potential advantage compared to current drugs in terms of higher efficacy and lesser toxicity.
Four were the objectives at the beginning of this translational project:

Objective 1: Molecular mechanism underlying the altered PE:SM ratio in tumoral cells. Several simple and multiple point mutant were generated for SGMS1 and 2, with focus on several specially relevant for initial experiments, while enzyme isoform location still will require further improvement. In addition a genome-wide RNAseq experiment provided us massive information on the gene expression pattern change under Minerval treatment.

Objective 2: Domains in SGMS interacting with Minerval. The use of [3H]-Minerval allowed us to describe that Minerval binds preferentially to a fraction enriched in SGMS1. Gain-of-function and loss-of-function experiments with both SGMS1 and SGMS2 in the glioma cell line U118 unveiled a specific and antagonist role for each of these proteins in cell proliferation.

Objective 3: Molecular pathway implicated in SGMS regulation. On one hand, the analysis of the splicing isoforms of SGMS1 unveiled a particular pattern for cell lines responding to Minerval. On the other hand, the rationale basis for the design of new drugs was established.

Objective 4: the design of new drugs targeting SGMS1 and SGMS2 for antitumor therapy. Two new formulations of Minerval were designed, synthesized and are been tested in in vitro cell proliferation assays.

Indeed, the knowledge gained with this project about Minerval’s molecular mechanism of action will be crucial to support the marketing application to the EMA and FDA and for the design of new anticancer compounds. In this scenario, the Membrane Lipid Therapy approach reveals a high potential not only from Minerval, but also because new drugs than can be designed during this project.

Concerning the contribution to European excellence and European competitiveness, this project met several aims of Seventh Framework Programme in the Health Area: Focus 1 (Biotechnology, generic tools and medical technologies for human health: Innovative therapeutic approaches and interventions); Focus 2 (Translating research for human health: Cancer); Focus 3: (Optimizing the delivery of health care to European citizens: Appropriate use of new health therapies and technologies).
The proposed research benefited from the infrastructure and resources at the Universitat de les Illes Balears (UIB) and its close relation to the academic spin-off Lipopharma. Lipopharma arose to turn new breakthrough scientific discoveries by reputable scientists at the UIB into a new class of innovative lipid regulator therapeutics. Lipopharma aims to develop next generation medicines, nutraceutical and cosmetic products, on the basis of the novel MLT strategy. Carrying out this research at the edge between academy and industry implies that the results were directly relevant to the, both private and public, scientific community that supported this research and is interested in applying it, therefore ensuring impact and medical benefit in the near future.
Regarding EMA’s classification of Minerval as orphan drug, in 2012, orphan drug sales were worth around €65 billion compared to overall prescription drug sales (excluding generics) of €483 billions (that is, 13%). The orphan drug market is expanding faster than traditional pharmaceuticals with annual growth averaging 26% from 2001 to 2010, compared with 20 per cent for non-orphan drugs (Meekings et al, 2012). Temozolomide, which only extends the life of patients in 10 weeks, sells around 1,000 Million Euros per year (last IP) protection years, so that it would be expected that this compound, developed in the EU, would have similar sales, providing not only a better quality of life and possibly a greater life expectancy to patients but also will generate jobs and funds to the University of the Balearic Islands and its spin off company, contributing to the economy of our community.
Hence, the benefits of exploiting the secondary structures in plasma membrane in living cells as therapeutic targets are just starting to be revealed. Not only Minerval has revealed promising in therapy against solid tumours but also a whole variety of conditions, including neurodegenerative disorders, inflammatory and metabolic diseases, can benefit from Membrane Lipid Therapy. Indeed with this project, the researcher contributed to future positive outcomes in terms of enhanced European scientific excellence, drug discovery, patentable research and clinical applications. Last but not least, Membrane Lipid Therapy approach is genuine from Europe; and funding this proposal means maintaining EU in its position at the leading edge of this technology.

Reported by

UNIVERSITAT DE LES ILLES BALEARS
Spain
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