Targeted therapies interfere with specific molecules involved in disease, representing a shift toward precision-based medicine. Within this landscape, a protein known as Ubiquitin-Specific Protease 7 (USP7) has emerged as a focal point for developing new cancer treatments due to its role in cellular processes.
The Role of USP7 in Cellular Health
Every cell uses a “recycling system” to maintain its health, known as the ubiquitin-proteasome system. This process involves tagging old or damaged proteins with a small molecule called ubiquitin. This tag marks the protein for destruction by a cellular machine called the proteasome, ensuring unwanted proteins are cleared away.
Within this system, USP7 is a deubiquitinating enzyme (DUB). Its job is to remove ubiquitin tags from specific proteins, rescuing them from destruction. By cleaving the ubiquitin marker, USP7 counteracts the degradation process and stabilizes its target proteins, allowing them to function within the cell.
Two proteins regulated by USP7 are the tumor suppressor p53 and its negative regulator, Mouse Double Minute 2 homolog (MDM2). The p53 protein helps prevent tumor formation by stopping cell division or initiating cell death when DNA damage is detected. MDM2 keeps p53 in check by tagging it for destruction, and USP7 maintains this balance by deubiquitinating both proteins.
Mechanism of USP7 Inhibition
A USP7 inhibitor is a small molecule engineered to block the USP7 enzyme. These molecules fit into the protein’s active site, the region responsible for removing ubiquitin tags. By obstructing this site, the inhibitor prevents USP7 from performing its deubiquitinating function.
The direct biochemical result of this inhibition is that USP7 can no longer save its target proteins from the proteasome. Without USP7’s intervention, proteins that it would normally stabilize, such as MDM2, remain tagged with ubiquitin. The proteasome recognizes these tagged proteins and breaks them down, lowering their concentration within the cell.
This targeted degradation of MDM2 is a primary consequence in many therapeutic models. The reduction of MDM2 levels disrupts the balance USP7 normally oversees. This sets off a chain reaction that impacts other proteins, creating changes that can be harnessed for therapeutic purposes.
Recent studies have also uncovered a mechanism independent of p53. Research indicates that USP7 helps control the cell cycle, preventing division until genetic material is copied. In this context, inhibitors trigger premature activation of the CDK1 protein, leading to uncontrolled cell division, DNA damage, and cell death.
Therapeutic Applications in Oncology
In oncology, USP7 inhibition exploits the cell’s own machinery to fight cancer. The primary therapeutic approach leverages the degradation of MDM2 to reactivate the p53 tumor suppressor protein. In many cancer cells where USP7 is overexpressed, inhibiting it shifts the cellular balance.
With MDM2 levels reduced, the p53 protein is freed from its suppressor and accumulates within the cancer cell. Elevated levels of active p53 can then initiate apoptosis, or programmed cell death. This approach is particularly promising for tumors that retain a functional, or “wild-type,” version of the p53 gene.
USP7 inhibitors are also explored for their ability to enhance other cancer treatments. They may make cancer cells more vulnerable to chemotherapy or radiation by interfering with DNA damage repair pathways. In immunotherapy, inhibiting USP7 can make tumors more recognizable to the immune system, for instance by affecting the PD-1/PD-L1 pathway.
The applications of USP7 inhibition are being investigated across a variety of cancer types. Preclinical studies have shown promise in:
- Multiple myeloma
- Acute myeloid leukemia
- Neuroblastoma
- Prostate cancer
In prostate cancer, its inhibition could disrupt signals that drive tumor growth. In certain breast cancers, USP7 promotes carcinogenesis through the USP7/PHF8/cyclin A2 axis, making it a viable target.
Current Research and Clinical Development
USP7 inhibitors are in experimental and clinical trial phases. While no inhibitor has received final approval for widespread clinical use, several candidates are progressing through clinical evaluation. Researchers are working to translate encouraging laboratory results into safe and effective treatments.
A focus of current research is identifying which cancers are most likely to respond. Clinical trials are investigating USP7 inhibitors in patients with advanced solid tumors and blood cancers. Scientists are analyzing tumor genetic profiles to find biomarkers that predict a patient’s response, such as the presence of a functional p53 gene.
Researchers are also addressing several challenges. One area of focus is ensuring the high specificity of the inhibitors to avoid off-target effects that could lead to toxicity. Another challenge is understanding and overcoming potential mechanisms of drug resistance that cancer cells might develop.