Neuroendocrine tumors novel treatment through blocking the endocannabinoid system

Overview

Neuroendocrine neoplasms (NENs) are rare heterogeneous tumors originating from cells with neuroendocrine phenotype and mostly developing in the gastrointestinal tract, pancreas, and lung. The majority of NENs patients present at advanced stages of metastatic disease, diagnosed incidentally or due to symptoms related to the tumor mass; only a minority of NENs patients are diagnosed earlier due to specific hormonal hypersecretion-related symptoms. NENs diagnosis and treatment are complex because of their heterogeneous biological behavior even inside the same tumor-subgroup classification. Cure by surgery is possible only for the small group of patients with localized disease; unresectable NENs patients are offered a variety of non-curable therapeutic options (somatostatin analogues, peptide receptor radio-ligand therapy, targeted agents, chemotherapy), with tumor control for limited periods of time. These treatments eventually fail due to the development of drug resistance, highlighting the grave need to searching for new therapeutic avenues in NENs, and to improve NENs patients’ survival. The most used drug to treat NEN is Everolimus (Afinitor®), an mTOR inhibitor that forces NEN cells to undergo autophagy. This modality fails overtime due to drug resistance. 

Noteworthy, the above therapies have limited effect as the cancer re-starts to grow after ~6-14 months due to development of drug resistance.

Our solution

Researchers from Hadassah Medical Center and the Hebrew University of Jerusalem found that NEN cells uniquely express some of the endocannabinoid receptors, and through their constitutive activation promote glycolysis (a phenomenon called the Warburg effect). By blocking the endocannabinoid pathway together with everolimus, a synergistic effect was achieved, thus promoting NEN autophagy concomitant with preventing glycolysis stress, culminating in resilient NEN cell death. The lower doses of everolimus in this combination therapy may also result in the reduction of the severe side effects of this drug.

Application

Neuroendocrine neoplasms (NENs) treatment

Market size

The economic burden of NEN patients is significantly higher than the average cost of other cancers, with a mean annual cost of over $70,000 compared to a national average of ~$38,000 among all cancers in the first year. The global neuroendocrine tumors drug market is valued at $1.45B in 2019 and is projected to grow at a CAGR of 10.6% until 2027, reaching $3.2B.

Development Status

Efficacy was shown in several in vivo models. NEN cell models treated with cannabinoid receptor antagonists in combination with everolimus supported the biological backbone of the treatment.

Intellectual Property

PCT filing

References:

On request