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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 specifically 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 (including MAP Kinases, Pi3K/AKT/MTor, PKC/Cyclin CDK or Notch pathways) is exhibited in at least one third of all human cancers.

 

Activation of SMS1 in cancer cells induces marked increases in its main product (SM), accompanied by reductions in the levels of its main substrates (PC and PE), causing “normalization” of membrane levels of PE, PC, PS and SM. By contrast, LP561A1 does not significantly alter membrane lipid composition in non-tumour cells, because the enzyme product (SM) is found already in high levels and its substrates are limiting.

 

Increases of SM and DAG products and reductions in PC, PS and PE in cancer cells plasma membranes induce the translocation of K-Ras from its active domain in the plasma membrane to the cytosolic membranes and inhibits its nanoclustering, short-cutting (normalizing) Ras signalling and 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) by increasing SM levels at the Plasma Membrane (PM) has also been proposed by an 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 increase of SM levels 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 can be found in this scientific publication:

 

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 preclinical studies strong correlation has been confirmed between levels of SMS1 and HES1 (Transcription factor of the Ras & Notch pathway) and anticancer effect of LP561A1, which demonstrates selectivity of anticancer effect, confirms the proposed MOA (SMS1 activation and Ras signalling inhibition) and provides preliminary rational for patient selection criteria to be validated in the clinical development.

 

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 (3 to 6 times) the expected therapeutic range.

 

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

 

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.

For more detailed information, visit clinicaltrials.gov

Other relevant related documents:

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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