LP561A1 (2OHOA) 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.


LP561A1 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.

LP561A1 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 (LP561A1), 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 LP561A1 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 page

Other relevant related documents:

icon The Opposing Contribution of SMS1 and SMS2 to Glioma Progression and Their Value in the Therapeutic Response to 2OHOA (1.26 MB) Fernandez-Garcia et al. Cancers, Jan 2019

icon Regulation of the cancer cell membrane lipid composition by NaCHOleate: effects on cell signaling and therapeutical relevance in glioma (1 MB) Lladó et al. Biochim Biophys Acta. Jun. 2014

icon Sustained activation of sphingomyelin synthase by 2-hydroxyoleic acid induces sphingolipidosis in tumor cells (1.03 MB) Martin et al. Journal of Lipid Research, Mar. 2013


icon The role of membrane fatty acid remodeling in the antitumor mechanism of action of 2-hydroxyoleic acid (1.99 MB) Martin et al. BBA Biomembranes, Jan. 2013


icon Normalization of sphingomyelin levels by 2-hydroxyoleic acid induces autophagic cell death of SF767 cancer cells (265.01 kB) Terés et al. Autophagy, Oct. 2012


icon 2OHOA Induces ER Stress and Autophagy in Various Human Glioma Cell Lines (2.2 MB) Marcilla-Etxenique et al. PLOS One, Oct. 2012


icon 2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy (3.03 MB) Teres et al. PNAS, May 2012.


icon Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells cells and in 2-hydroxyoleic acid therapy (1.31 MB) Barcelo-Coblijn et al. PNAS, Dec. 2011


icon Pivotal role of DHFR knockdown in the anticancer activity of 2-hydroxyoleic acid (1.11 MB) Llado et al. PNAS, Aug. 2009


icon 2OHOA induces apoptosis in Jurkat and other cancer cells (1.09 MB) LLado et al. Journal of Cellular and Molecular Medicine, Dec. 2008


icon The Repression of E2F-1 Is Critical for the Activity of 2OHOA against Cancer (397.05 kB) Martinez et al. The Journal of Pharmacology and Experimental Therapeutics, Jul. 2005



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