RESEARCHERS DISCOVER POSSIBLE NEW TREATMENT FOR TRIPLE-NEGATIVE BREAST CANCER

Researchers from the Molecular and Cellular Oncogenesis Programme of the Ellen and Ronald Caplan Cancer Centre at The Wistar Institute have published a new paper in the journal Nature Cancer that demonstrates a double-acting mechanism for fighting a particularly aggressive, difficult-to-treat form of breast cancer. The study shows how silencing a certain gene, ACSS2, may improve existing treatments for patients.

Triple-negative breast cancer, or TNBC, is so named because the cancer lacks an oestrogen receptor, a progesterone receptor, and a HER2 (human epidermal growth factor) receptor. The absence of any of these receptors - receptors that when present in other forms of breast cancer, can be effectively targeted during treatment - makes treating TNBC rather difficult, and patients with TNBC have limited treatment options.

TNBC’s notorious aggression makes the technical challenge of finding a reliably effective treatment target all the more serious. Compared to other breast cancers, TNBC grows faster and resists treatment more stubbornly. All these factors contribute to the fact that TNBC patients suffer from worse prognoses.

In the new study, the scientists demonstrated the efficacy of a double-acting concept: silencing the gene ACSS2 impairs TNBC metabolism, while simultaneously boosting the immune system’s ability to fight it. ACSS2 regulates acetate, a nutrient that cancer cells - TNBC cells in particular - take advantage of to grow and spread. The team used two methods to deactivate ACSS2: CRISPR-Cas9 gene editing, and the compound VY-3135, a potent ACSS2 inhibitor identified by the team in 2021.

The researchers found that targeting ACSS2 not only hampered TNBC’s ability to metabolise acetate and grow, it also triggered the immune system to recognise and attack the cancer. Because cancer cells with inhibited ACSS2 cannot process acetate very well, the tumour region becomes bathed in acetate, which alerts the immune system of something amiss.

This process of guiding the immune system to the cancer called “immunosensitisation” - has confounded many TNBC researchers. However, the new approach showed that ACSS2 inhibition immunosensitised against TNBC so well that tumour growth was drastically reduced, even to the point of wiping out the cancer completely in some experiments.

Another group’s different ACSS2-inhibiting approach is in human clinical trials, and the team’s research shows how ACSS2-inhibiting treatment might be able to improve outcomes for patients diagnosed with the infamous TNBC. By testing ACSS2 inhibitors alongside standard anti-breastcancer chemotherapy, the researchers found that ACSS2 inhibition enhanced the treatment’s effectiveness.

The team concluded that ACSS2 was a promising target for TNBC and their research shows how the immune effects of ACSS2 inhibition could eventually be used in TNBC patients with limited treatment options. They added that while more research is needed, by combining this approach with other cancer therapies, they expect to see big improvements in treating TNBC.