A new experimental treatment that removes a key cancer-driving protein rather than simply blocking it may offer a powerful new option for people with breast cancer, especially those whose disease no longer responds to standard hormone therapy, according to a study published recently in Wiley Advanced.
Researchers report that two DNA-based drug candidates successfully eliminated SETDB1, a protein linked to tumor growth, drug resistance and immune system evasion, leading to slower cancer growth and better immune attack in laboratory and animal studies.
SETDB1 plays an important role in how cancer cells control genes that help them survive, spread and hide from the immune system. High levels of this protein have been associated with breast cancer progression and resistance to tamoxifen, a commonly used hormone therapy.
Until now, SETDB1 has been difficult to target with traditional drugs. The new approach uses PROTAC technology, which works by tagging harmful proteins so the cell’s own recycling system destroys them.
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The researchers designed PROTACs made entirely of short DNA strands called aptamers. One aptamer binds tightly to SETDB1, while another guides the drug into cancer cells and recruits a natural disposal system involving the MDM2 protein. Two versions were developed, called AP-SETDB1-S6A and AP-SETDB1-D2. Both were stable in blood-like conditions and were able to enter breast cancer cells without special delivery tools.
“The efficacy of PROTACs relies heavily on the specificity of target recognition,” explained the authors of this study. They continued, “Aptamers, with their high specificity and affinity, are increasingly explored as promising recognition moieties for PROTAC design.”
In multiple breast cancer cell lines, the PROTACs reduced SETDB1 levels in a dose- and time-dependent way. Importantly, they had little effect on normal breast cells, suggesting a degree of selectivity that could limit side effects. By removing SETDB1, the treatments slowed cancer cell growth, reduced their ability to migrate and invade and sharply decreased their ability to form new colonies.
The treatment also addressed a major clinical problem: drug resistance. In breast cancer cells that no longer responded to tamoxifen, lowering SETDB1 restored sensitivity to the drug. In addition, cancer cells treated with the PROTACs became more vulnerable to attack by CD8+ T cells, indicating that the therapy may help the immune system better recognize and kill tumors.
In mice with breast cancer tumors, both PROTACs accumulated in tumor tissue, slowed tumor growth and reduced markers of cancer cell division without causing weight loss or organ damage. While these findings are early and human trials are still needed, the study suggests that targeted removal of SETDB1 could one day lead to more effective and personalized treatments for patients with breast cancer, particularly those facing drug resistance.
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