Minerval (LP561A1)

Minerval (2OHOA, LP561A1) is the first-in-class anticancer drug acting through cell membrane lipid modification. It can be categorized as a sphingomyelin synthase 1 (SMS1) activator with Ras signalling modulator effects

Minerval is an orally bioavailable synthetic derivative of oleic acid that crosses de Blood Brain Barrier and activates SMS1, a key enzyme that catalyses the reversible conversion of PC, PE, PS and Cer into SM and DAG at the plasma membrane. Membrane lipid composition and organization is known to be significantly altered in cancer cells and it has been observed that these changes are enabling increased recruitment to the cell membrane of central proliferation signalling proteins, such as K-Ras. Aberrant activity of Ras-associated proliferative signalling pathways is found in at least one third of all human cancers.

2OHOA increases SM and DAG products and reduces PC, PS and PE levels in cancer cells membranes, inducing the translocation of K-Ras from its active domain in the plasma membrane to the cytosolic membranes and inhibits its nanoclustering and signalling, inactivating key Ras-dependent proliferation pathways (like Ras/MAPK, Pi3K/AKT/mTOR or PKC/Cyclin CDK), causing cell cycle arrest followed by selective death of cancer cells.

Interestingly, the scientific rational of this same approach, involving the control of H-Ras & K-Ras localization (and signalling) has also been proposed by a prestigious independent research group at the Medical School of the University of Texas Health Science Center, in Houston, leaded by Prof John F. Hancock. In this case the effect is achieved with the aid of an acid sphingomyelinase (ASM) inhibitor (fendiline) instead of using an SM synthase activator (2OHOA), but the final results are the same in terms of reorganization of membrane lipids and impact on K-Ras localization and nanoclustering. Main description of this Mechanism of Action proposed by Prof. Hancock's group, including an independent confirmation of K-Ras activity modulation by 2OHOA can be found in the following scientific publications:

Sphingomyelin metabolism is a regulator of KRAS function. Van der Hoeven et al. Molecular and Cellular Biology. Nov. 2017

Inhibition of Acid Sphingomyelinase Depletes Cellular Phosphatidylserine and Mislocalizes K-Ras from the Plasma Membrane. Cho et al. Molecular and Cellular Biology. Jan. 2016

In addition, a recent publication by an independent research group characterizes the key role of membrane-lipid reorganization (as observed with 2OHOA treatment!) in the increased proliferation of T-cells and activation of the immune system against the tumors.

Enhanced Acid Sphingomyelinase Activity Drives Immune Evasion and Tumor Growth in Non-Small Cell Lung Carcinoma. Kachler et al. Cancer reserach Nov. 2017

The European Medicines Agency designated 2OHOA as an orphan medicinal product for the treatment of glioma in October 2011 (EU/3/11/916)

A comprehensive non-clinical program has characterized the safety and toxicity of 2OHOA across a host of animal models. Current clinical investigations have also found the product to be safe and well-tolerated in adult patients, even at doses well above the expected therapeutic range.

A phase I/IIa clinical trial with 2OHOA in Adult Patients with Advanced Solid Tumours including Malignant Glioma (MIN-001-1203) has already been completed with very encouraging results: no relevant drug-related toxicities found (other than anticipated reversible gastrointestinal effects at very high doses) and very promising clinical activity confirmed in several patients, including recurrent glioblastoma patients. A poster with a summary of the final results of the MIN-001-1203 study with 2OHOA was presented at ASCO 2017. ::> Download the poster here

Further clinical trials with Minerval in paediatric population with malignant glioma and other advanced solid tumours (MIN-001P-1501), and in adult patients with newly-diagnosed glioblastoma (MIN-002-1801 and MIN-003-1806) are under preparation in the USA and in Europe.

For more detailed information, visit the Clinical Trials section

Relevant related documents:

- The Opposing Contribution of SMS1 and SMS2 to Glioma Progression and Their Value in the Therapeutic Response to 2OHOA. Fernandez-Garcia et al. Cancers, Jan 2019

- Minerval (2-hydroxyoleic acid) causes cancer cell selective toxicity by uncoupling oxidative phosphorylation and compromising bioenergetic compensation capacity. Massalha et al. Biosci_Rep. Jan 2019

- Regulation of the cancer cell membrane lipid composition by NaCHOleate: effects on cell signaling and therapeutical relevance in glioma. Lladó et al. Biochim Biophys Acta. Jun. 2014

- Sustained activation of sphingomyelin synthase by 2-hydroxyoleic acid induces sphingolipidosis in tumor cells. Martin et al. Journal of Lipid Research, Mar. 2013

- The role of membrane fatty acid remodeling in the antitumor mechanism of action of 2-hydroxyoleic acid. Martin et al. BBA Biomembranes, Jan. 2013

- Normalization of sphingomyelin levels by 2-hydroxyoleic acid induces autophagic cell death of SF767 cancer cells. Teres et al. Autophagy, Oct. 2012

- 2-Hydroxyoleic acid induces ER stress and autophagy in various human glioma cell lines. Marcilla-Etxenique et al. PLOS One, Oct. 2012

- 2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy. Teres et al. PNAS, May 2012.

- Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells. Barcelo-Coblijn et al. PNAS, Dec. 2011

- Pivotal role of DHFR knockdown in the anticancer activity of 2-hydroxyoleic acid. Llado et al. PNAS, Aug. 2009

- 2OHOA induces apoptosis in Jurkat and other cancer cells. Llado et al. Journal of Cellular and Molecular Medicine, Dec. 2008

- The repression of E2F-1 is critical for the activity of Minerval against cancer. Martinez et al. The Journal of Pharmacology and Experimental Therapeutics, Jul. 2005

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