“In T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematologic cancer with poor clinical outcomes, more than 50% of cases show NOTCH1-driven transformation [1]. The NOTCH1 receptor signaling pathway is activated through a series of proteolytic cleavages, ultimately causing the release of the active intracellular domain (NICD), which translocates to the nucleus where it promotes transcription of target genes involved in cell growth. The importance of NOTCH1 mutations in T-ALL has generated great interest in the development of anti-NOTCH1 targeted therapies.

A new and promising emerging field in cancer treatment is medical cannabis. Accumulating evidence suggests the direct effects of cannabis on tumor progression in cell lines and animal models [2]. Cannabis, and its unique secondary metabolites, known as phytocannabinoids, directly affect the propagation of cancer cells by modulating key cellsignaling pathways.

We have previously demonstrated that different cannabis extracts, each containing a unique composition of metabolites, selectively impaired the survival of cancer cell lines depending on a match between the chemical composition of the extract and the characteristics of the specific cancer cell line.

In the present work, we set out to investigate whether cannabis extracts with unique phytocannabinoid profiles can selectively facilitate antitumor effects in T-ALL cells that harbor a Notch1 mutation.

In summary, targeting NOTCH1 signaling has generated much interest for its therapeutic potential. However, so far, efforts to develop such treatments have been unsuccessful.

The cannabis plant contains over 140 phytocannabinoids, many of which are presumed to have pharmacological properties, and accumulating evidence suggests anticancer capabilities.

Here, we identified a specific CBD-rich extract that selectively induced apoptosis in NOTCH1-mutated T-ALL cells. Although CBD by itself was able to induce cell death, the whole extract was more effective, suggesting that other metabolites from the plant are required to achieve full potency.

We have previously demonstrated this phenomenon in a mouse model of epilepsy, where CBD-rich extracts with equal amounts of CBD but varying concentrations of other minor compounds led to diverse anticonvulsant effects. A possible mechanism previously suggested to explain the difference between the effects of purified phytocannabinoids versus full-spectrum extracts is the “entourage effect”, where one compound may enhance the activity and efficacy of another on the same target. While this synergy is well-established for endogenous cannabinoids of the endocannabinoid system, only very few studies demonstrated this phenomenon for phytocannabinoids.

Cannabis is already being prescribed to cancer patients for its palliative qualities; however, the huge variety between different chemovars in their composition is disregarded. Matching an effective extract to certain cancer subtypes will ultimately lead to personalized cancer treatments and medications that not only treat symptoms but also treat the disease.

As dysregulation of NOTCH1 signaling has been found in various cancers other than T-ALL and in non-cancerous diseases, our findings suggest a novel therapeutic strategy for the effective treatment of a variety of malignancies.”

https://pubmed.ncbi.nlm.nih.gov/37086009/

https://onlinelibrary.wiley.com/doi/10.1002/cac2.12422