A groundbreaking discovery in the fight against breast and ovarian cancers has emerged from the laboratories of Baylor College of Medicine, showcasing the potential of a small molecule called 5D4 to combat these challenging malignancies in mouse models. Published on October 25 in the Proceedings of the National Academy of Sciences, this study introduces a promising therapeutic avenue by inhibiting TopBP1, a gene considered notoriously difficult to target directly.
Researchers at Baylor College of Medicine unveiled compelling evidence that 5D4, categorized as a TopBP1 inhibitor, has the capacity to arrest the growth of breast and ovarian tumors in mouse models. Strikingly, when combined with Pfizer’s PARP 1/2 inhibitor, Talzenna (talazoparib), the efficacy of 5D4 was significantly enhanced, marking a remarkable advancement in cancer treatment.
Dr. Fang-Tsyr Lin, co-author of the study, expressed the significance of this discovery, stating, “It’s very exciting to have found a TopBP1 inhibitor that really stops cancer growth in cells and in animal models in the lab.”
The origins of this breakthrough can be traced back over a decade of research on TopBP1, a pivotal protein at the crossroads of multiple pathways implicated in cancer development. Among these pathways, TopBP1 plays a crucial role in regulating the expression of MYC, a gene linked to more than half of all human cancers. Elevated MYC levels are associated with poorer outcomes in various cancer types, including breast, blood, and lung cancers. However, directly targeting MYC has proven to be a formidable challenge.
Researchers at Baylor College of Medicine were inspired by prior studies indicating that inhibiting TopBP1 had the unexpected effect of enhancing the expression of another gene, MIZ1, which, in turn, restricts MYC’s cancer-promoting abilities. This revelation led to the hypothesis that augmenting MIZ1 activity could counteract MYC’s oncogenic effects, potentially offering a therapeutic strategy.
To put this theory into practice, the research team needed to identify a drug capable of precisely targeting the TopBP1 protein. After a rigorous screening of thousands of compounds using a technique called molecular docking, they identified 5D4 as the ideal candidate.
The next step involved validating 5D4’s anti-TopBP1, anti-MYC, and anti-cancer properties in cell studies, paving the way for experiments in mice. Two separate groups of mice were injected with ovarian cancer and breast cancer cells, followed by doses of either 5D4 or a control solution administered every three days. The results were remarkable – 5D4 effectively reduced tumor growth in both models compared to the control group. Even in a more aggressive breast cancer model with high MYC expression, 5D4 exhibited its efficacy.
Building on evidence suggesting that a TopBP1 inhibitor would synergize with PARP inhibitors, the researchers combined 5D4 with talazoparib in mouse models of breast cancer, including one that displayed resistance to PARP inhibitors. The combination therapy outperformed 5D4 alone, offering a higher degree of tumor growth inhibition. Importantly, tumors that were resistant to talazoparib remained responsive to 5D4. Remarkably, no apparent side effects were observed in the mice during these experiments.
While the study involved immunocompromised mouse models, researchers anticipate that combining a TopBP1 inhibitor with a PARP inhibitor might yield even more favorable results in an intact immune response. This potential avenue deserves further exploration, as researchers aim to advance 5D4 for use in humans, optimize its anti-tumor effects in combination with other drugs, and minimize potential toxicities. This breakthrough promises new hope in the fight against breast and ovarian cancers, offering a more targeted and effective treatment approach.
