A new study led by Dr. Zachary Schug at The Wistar Institute has identified a promising double-acting mechanism for addressing triple-negative breast cancer (TNBC), a particularly aggressive and difficult-to-treat form of the disease. TNBC lacks estrogen receptors, progesterone receptors, and HER2 receptors, which makes traditional treatments less effective. This form of breast cancer also grows faster and is more resistant to treatment, resulting in worse prognoses for patients.
Dr. Schug and his team focused on silencing a specific gene, ACSS2, which plays a role in TNBC metabolism. When ACSS2 is silenced, TNBC cells struggle to metabolize a key nutrient called acetate, hindering their growth and spread. Additionally, inhibiting ACSS2 has the unintended consequence of alerting the immune system to the presence of cancer cells.
The researchers used two methods to deactivate ACSS2: CRISPR-Cas9 gene editing and a potent ACSS2 inhibitor called VY-3-135. In their preclinical study, they found that inhibiting ACSS2 not only impaired TNBC metabolism but also triggered the immune system to recognize and attack the cancer. The tumor region, unable to process acetate efficiently without ACSS2, released large amounts of acetate, which acted as a signal for the immune system.
This process, known as “immunosensitization,” proved highly effective in reducing tumor growth and even eliminating the cancer in some cases. The immune system’s memory of the cancer remained intact even when the ACSS2 gene was still active in the tumor.
The research suggests that ACSS2 inhibition, when combined with standard anti-breast-cancer chemotherapy, could improve outcomes for TNBC patients. Another group is currently testing a different ACSS2 inhibitor in human clinical trials. This promising approach can potentially provide new treatment options for TNBC patients who have limited options.
Further research is needed, but this study demonstrates the potential for combining ACSS2 inhibition with other cancer therapies to enhance the effectiveness of treatments for triple-negative breast cancer.
– Katelyn D. Miller et al, Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer, Nature Cancer (2023).