A team of researchers has for the first time recently demonstrated the anti-tumor effect of dendrogenin A, a cholesterol derivative, on human cancer cells. A discovery that paves the way for new possibilities in the treatment of cancer which involve acting on cellular mechanisms that, up until now, have not been targeted.
For several years, Marc Poirot, Sandrine Silvente-Poirot, and their team at the Cancer Research Center of Toulouse (CRCT)* have been conducting research into dendrogenin A (DDA), a molecule which is naturally present in the body and derived from the transformation of cholesterol. In an initial study published in 2013, they observed that this molecule was present in large quantities in healthy tissue but absent in tumor cells, a finding confirmed in animals, on melanoma cells and on breast cancer cells. In addition, the study revealed DDA to have an anti-cancer effect. "We were unable to demonstrate whether the molecule was effective on a human tumor," states Poirot. "So we continued our research to determine its mechanism of action and to evaluate the possibility of testing its efficacy in humans."
In an article recently published in Nature Communication, the researchers report the molecule’s efficacy on cells from two types of human cancer: melanoma and acute myeloid leukemia. Furthermore, they describe its mechanism of action, which is quite novel in comparison with the molecules conventionally used in the treatment of cancer.
"We observed very early on that DDA led to autophagy – a kind of cannibalism – in tumor cells: they eat themselves and, as a result, die," explains Poirot.
Autophagy is a physiological process used by the cell in order to survive when starved of nutrients. Over-activation of this process – for example by DDA – leads to tumor cell death.
Two mechanisms leading to the stimulation of autophagy
The research described in this new paper show that DDA acts on autophagy via two mechanisms of action:
Firstly, the molecule is capable of binding to the nuclear receptor LXR. This receptor controls the activity of a family of genes implicated in autophagy, notably LC3, Nur77, Nor1, and TFEB. Its suppression induces a loss of DDA action on autophagy. This result was observed in vitro in cell cultures, but also in vivo with cells implanted in mice.
Secondly, DDA inhibits an enzyme, D8D71, provoking the accumulation of a molecule that favors the development of autophagy. When combined with the stimulation of the aforementioned genes, this effect increases the cytotoxic autophagic effect.
Clinical trials within one to two years' time
This discovery of DDA's mechanism of action opens up new therapeutic avenues that the researchers have begun to envisage. The molecule is now being produced by a biotech lab for future therapeutic applications. An evaluation program will commence in the near future. Poirot considers that "this molecule should be able to be used by patients in a clinical trial setting within one to two years’ time. We think that it could be effective on a certain number of cancers, either alone or in combination with existing molecules, provided that the LXR receptor is expressed."
Beyond the clinical aspects, this discovery also offers potential for fundamental research. Future work in this domain will look at the gene coding for the enzyme responsible for DDA biosynthesis and at the processes involved in controlling the mechanisms of autophagy. The aim: to understand how this control can lead to normal or pathological situations.
* Unit 1037 Inserm/Université Toulouse III, Cholesterol metabolism and therapeutic innovations team, Cancer Research Center of Toulouse (CRCT)
G. Segala et al. Dendrogenin A drives LXR to trigger lethal autophagy in cancers. Nature Communications 8, 1903 (2017) doi:10.1038/s41467-017-01948-9