New Approach to Endocannabinoid System Signaling May Help in Prostate Cancer

FABP Fatty Acid Binding Protein Modulates Endocannabinoid System, New Strategy in Cancer Research

The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays an important role in the development of the human central nervous system, synaptic plasticity and the response to endogenous and environmental stresses. Numerous scientific publications have shown its importance in human physiology as a modulator of cardiovascular, gastrointestinal and immune function, metastatic transformation, and key aspects of central nervous system function, including movement disorders, pain and behavior. The endocannabinoid system is therefore an attractive and validated target for pharmacological intervention. Modulating the endocannabinoid system for its vast therapeutic potential is one of the most promising areas of current research strategies

Along with the development of phytocannabinoids for medical purposes, another technique of pharmaceutical companies is to increase the level of endocannabinoids likeanandamide (AEA) in our body. A first identification has been approached previously by inhibiting the degradation enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol, MGL) that break down the anandamide endocannabinoids. These animal studies have shown that elevated levels of the endocannabinoids anandamide may have beneficial pharmacological effects on stress, pain and inflammation, and may reduce the withdrawal effects of a drug.

Une nouvelle alternative strategy first demonstrated by researchers at Stony Brook University in collaboration with the company Artelo Biosciences focused his research on targeting the intracellular transport mechanisms that bring endocannabinoids to these degrading enzymes. Artelo's commercial model consists in developing multiple pharmacological approaches to the modulation of the endocannabinoid system based on the targeting of cannabinoid receptors and on the inhibition of endocannabinoid transport.

Because endocannabinoids are fatty molecules, they are transported in the aqueous intracellular environment by proteins called fatty acid binding proteins (FABP).

Following this approach, Stony Brook researchers developed specific inhibitors of FABP5 through a combination of virtual screening, bioassays and medicinal chemistry, which are now exclusively licensed from Artelo. Over the past two years, Artelo and Stony Brook have worked together to develop third-generation chemicals that are more selective and potent FABP5 inhibitors suitable for federally regulated drug development under an exclusive agreement and in collaboration with the Research Foundation of the State University of New York Stony Brook, the company Artelo is developing an inhibitor from the Fatty Acid Binding Protein 5 (FABP5) this program is called ART26.12. for the treatment of cancer, inflammation and pain.

New frontier in understanding the endocannabinoid system?

Preclinical data shows that inhibition of FABP5 may have therapeutic utility in areas typical of cannabinoid therapy, including pain, inflammation, and cancer. Unlike FAAH inhibition, selective targeting of FABP5 could have fewer off-target risks and therefore a potentially higher safety profile.

Fatty acid binding proteins have been identified such as intracellular transporters of the endocannabinoid anandamide (AEA), a neurotransmitter produced in the brain. Inhibition of FABP5 is expected to lead to higher levels of AEA and may have significant potential in the treatment of pain.

A series of studies at Stony Brook have shown that first generation ART26.12 has analgesic effects in several different pain models that are inhibited by antagonism of CB1 and TRPV1 and PPAR , via AEA and endocannabinoid type molecules palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are also transported by FABP5 to FAAHs to be degraded there (see FIG. 1). Inhibition of FABP5 is particularly effective in models of inflammatory pain, where ART26.12 decreases prostaglandins and pro-inflammatory cytokines in addition to direct analgesic effects.

(Figure 1 : FABP5 and PPARβ / δ are critical mediators of epidermal growth factor receptor-induced carcinoma cells. Researchers identified that overexpression of FABP5 increased uptake and hydrolysis of AEA, while inhibition of FABP5 increased levels of AEA. Their data showed that FABP5 supplies AEA to FAAHs for their degradation.

The encouraging analgesic and anti-inflammatory results seen with ART26.12 mean that this program could represent an important advance in the treatment of pain and inflammation. Important potential advantages over current therapies include the low potential for opioid dependence, as well as the wide application in the field of chronic pain, cancer pain and neuropathic pain.

In addition to modulating the tone of endocannabinoids, inhibition of FABP5 affects cell fate of fatty acids, which is particularly relevant in cancers such as prostate cancer and breast cancer. In particular, FABP5 has been extensively shown to be overexpressed in prostate cancer and to correlate with worsening prognosis and patient survival rates. Pharmacological inhibition of FABP5 reduces tumor size in mice injected with prostate cancer cells and decreases the spread of cancer to other areas such as the liver and lungs. Stony Brook's data showed that the more potent or more selective FABP5 inhibitors (SBFI102 and SBFI103) do not interfere with the anti-tumor actions of taxanes, the standard treatment for metastatic prostate cancer, but are able to work in synergy to cause even greater reductions in tumor growth than with either drug alone. Combining FABP5 inhibitors with lower doses of taxanes may lead to fewer side effects and a more tolerable experience for people being treated for prostate cancer.

Considering the encouraging anti-tumor and anti-metastatic results observed with ART26.12 and the synergistic potential demonstrated with standard therapies, ART26.12 should have wide application in vascular malignancies such as prostate cancer, breast, cervix and some types of melanoma.

ART26.12 paves the way for a new frontier of next generation compounds that take advantage of the growing understanding of how best to harness signaling from the endocannabinoid system. Inhibition of FABP5 is particularly new and has compelling preclinical data to support its potential use in the treatment of solid tumors, pain, and inflammatory conditions.

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