USP15 enzyme emerges as potential target for ovarian cancer treatment

Ovarian cancer is often diagnosed after it has already spread to other parts of the body, at which point the five-year survival rate is under 30 percent. Further complicating treatment, standard therapies cause substantial harm to healthy cells alongside cancerous ones. But what if ovarian cancer treatment could more specifically target cancerous cells, causing less harm to the rest of the body? New research from Achuth Padmanabhan's lab at the University of Maryland, Baltimore County (UMBC) offers hope in the form of a potential molecular target for new cancer drugs: an enzyme called USP15, which ovarian cancer cells appear to rely on more heavily than normal cells.

A serendipitous discovery

Like much of science, this discovery began serendipitously. As a postdoctoral fellow at Baylor College of Medicine, Padmanabhan was studying the protein p53, which in its normal form helps prevent tumor formation. Mutations in the gene that codes for p53 occur in nearly every case of the most common and lethal form of ovarian cancer, and are common across a wide range of cancer types.

Strengthening the story

Importantly, reducing USP15 made the cancer cells more vulnerable to the most common ovarian cancer treatment drugs, carboplatin and paclitaxel, and doxorubicin, a particularly toxic drug used to treat a range of cancers. With less USP15 present, lower doses of these drugs might achieve the same treatment effect with less toxicity.

Yet, reaching their conclusions wasn't always straightforward.

For example, a molecule that usually tracks with cell growth (indicating cancer progression) rose instead of falling in the presence of reduced USP15. On further investigation, the team discovered a different molecule associated with cell division that did go down. That combination suggested that with less USP15, cancer cells were still growing, but struggling to successfully divide. That led them to the discovery that the cancer cells were failing to properly separate their duplicated chromosomes during cell division.

Motivating further research

Moving forward, Padmanabhan's team wants to further reveal USP15's basic functionality, laying the groundwork for drug development work. For example, they want to learn what controls USP15 levels in cancer cells and whether inhibiting the enzyme can also reshape a tumor's immediate surroundings.

Even with that information, the need to figure out how to reduce USP15 levels safely in human patients will remain. The good news, Padmanabhan notes, is that molecules used to inhibit USP15 in laboratory experiments already exist and could be a starting point for developing human drugs.

"Hopefully," Padmanabhan says, "work such as ours demonstrating the potential of USP15 as an anti-cancer therapeutic target will motivate pharmaceutical companies and other research groups to pursue the development of clinically translatable USP15 inhibitors."

Source:

University of Maryland Baltimore County

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