Some breast tumors with certain genetic alterations are difficult to treat using existing therapies. Researchers at the University of Basel have now discovered an approach that involves a toxic combination with a second target gene in order to kill the abnormal cells. The first clinical trials could be starting soon.
A breast cancer diagnosis is the beginning of a long journey of treatments. Those affected are soon confronted with the fact that not all types of breast cancer are equal. Therapy depends strongly on the characteristics of the tumor tissue, such as the presence of certain hormone receptors and the defects of the abnormal cells. The estrogen-receptor-positive breast tumors include a group that are typically treated with hormonal therapies but frequently become resistant to such treatments over time.
Researchers led by Dr. Salvatore Piscuoglio from the Department of Biomedicine at the University of Basel and Dr. Charlotte Ng from the University of Bern have discovered a promising therapeutic approach for this subset of estrogen-receptor-positive breast tumors. The approach is based on the fact that the genetic defect in these cancer cells - a mutation in the GATA3 gene - makes them sensitive to switching off a second gene called MDM2. Healthy cells are not damaged when MDM2 is inhibited. In breast cancer cells with the GATA3 defect, however, the loss of MDM2 results in cell death, as the researchers report in the journal Communications Biology.
Active substances already exist
The fact that MDM2 could be a worthwhile target structure for the treatment of these breast tumors was revealed by a computational algorithm developed by Professor Niko Beerenwinkel at ETH Zurich in collaboration with the University of Basel researchers. This algorithm predicts pairs of genes whose loss does little damage individually but in combination is lethal to cells, and the program proposed MDM2 as a second component alongside GATA3. "MDM2 inhibitors already exist and are currently being used or tested in clinical trials for other types of cancer," explains Piscuoglio.
In various experiments with mini-tumors in a Petri dish and human breast cancer tissue in laboratory animals, for example, MDM2 inhibitors were shown to shrink the tumors. The researchers have since applied for a patent for their approach and now hope that the therapy can soon also be tested in clinical use. "MDM2 inhibitors have already been approved in the US for the treatment of certain types of cancer," says Piscuoglio, adding that this makes it easier to switch to use in breast cancer.
For the study that has now been published, the researchers from the University of Basel worked together with colleagues from ETH Zurich, the University of Bern, Institut Curie in France and Rain Therapeutics in the US.
Gaia Bianco et al.
GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers.
Communications Biology (2022), doi: 10.1038/s42003’022 -03296-x