UMBC Research Identifies USP15 Enzyme as Ovarian Cancer Target

Targeting USP15 in Ovarian Cancer

• Lowering USP15 levels in ovarian cancer cells slows tumor growth, prevents proper chromosome separation during cell division, and reduces tissue migration.
• Reduced USP15 expression makes cancer cells more vulnerable to common chemotherapy drugs including carboplatin, paclitaxel, and doxorubicin.
• The research originated from studying how mutant p53 proteins act as a stuck accelerator in cancer progression rather than a simple brake.

The Clinical Challenge of Ovarian Cancer

Ovarian cancer is frequently diagnosed after the disease has spread throughout the body, leaving patients with a five-year survival rate under 30 percent. Standard treatment regimens present a persistent clinical challenge because therapies like chemotherapy inflict substantial damage on healthy cells alongside malignant ones. Identifying vulnerabilities unique to or heavily relied upon by cancer cells remains a primary objective in drug development. The UMBC research addresses this gap by isolating an enzyme that cancer cells utilize to stabilize disease-driving mutant proteins.

Unraveling Mutant p53 and Enzyme Stability

The discovery began during earlier work at Baylor College of Medicine, where Padmanabhan studied the tumor suppressor protein p53. Mutations in the gene encoding p53 appear in nearly every case of the most common and lethal form of ovarian cancer. Rather than simply losing its tumor-suppressing function, two-thirds of p53 mutations in ovarian cancer convert the protein into a driver of cancer progression while extending its lifespan inside the cell. Padmanabhan discovered that the enzyme USP15 removes small molecular tags that normally mark proteins for destruction, thereby stabilizing the mutant p53 and sustaining tumor growth.

Laboratory Results Point to DNA Damage

When Padmanabhan established his lab at UMBC in 2019, and was joined by Ogunsanya in 2021, the team expanded the investigation into the broader role of USP15 in ovarian cancer. Through a series of cellular and mouse experiments, the researchers observed that reducing USP15 triggers multiple anti-cancer effects. In addition to slowing cell division and migration, lowering the enzyme causes chromosomes in cancer cells to fail to separate cleanly during division, directly generating fatal DNA damage.

Reducing Toxicity and Future Drug Development

Significantly, suppressing USP15 sensitizes ovarian cancer cells to standard therapeutic agents such as carboplatin and paclitaxel, alongside doxorubicin. This vulnerability suggests that future therapeutic strategies might achieve equivalent or superior clinical outcomes using lower doses of these highly toxic drugs, thereby mitigating adverse side effects for patients. Achieving these findings required overcoming experimental ambiguities, such as unexpected molecular tracking patterns that ultimately revealed how cancer cells struggle to divide successfully when USP15 is depleted.

Current molecules capable of inhibiting USP15 in laboratory settings provide a foundational starting point for future drug development. Next steps for the research team include defining the mechanisms that control USP15 levels inside cancer cells and examining whether enzyme inhibition alters the immediate environment surrounding a tumor. Investigators emphasize that motivating pharmaceutical companies to translate these laboratory findings into clinically viable human drugs is the essential next phase for the research.