Recent findings published in Scientific Reports highlight a promising target for ovarian cancer drug development, emphasizing the importance of Claudin-4 in tumor progression and resistance.
High-grade serous carcinoma (HGSC), a highly aggressive cancer that develops in the ovaries or fallopian tubes, is a malignancy often diagnosed in advanced stages. This disease grows robustly in a suppressive tumor microenvironment (TME). The TME encompasses the cells, proteins, and other immune mediators present in the tumor microenvironment. When high frequencies of immunosuppressive factors, including immune cells that downregulate anti-tumor immunity, localize to the TME, it can restrict anti-tumor immunity. An immunosuppressive state also correlates with tumor progression and therapeutic resistance, significantly thwarting outcomes for patients with HGSC. Only about 50% of women with HGSC achieve five-year survival due to the aggressive nature and therapeutic resistance of the disease.
The study identified Claudin-4 due to its overexpression in HGSC. Claudin-4 regulates the genetic material in cells by facilitating the initiation and resolution of genetic alterations. Genomic instability can influence the tumor's ability to evade immune surveillance and also interfere with treatment efficacy.
Using ovarian cancer models in the laboratory, the researchers compared the functions of cells with and without claudin-4. Next, using a mouse model that recapitulates the human immune system, the researchers tested the ability of a claudin mimic peptide (CMP) to treat ovarian tumors. The studies showed that claudin-4 regulated a class of immune regulators known as type I interferon.
When the researchers treated tumors expressing claudin-4 with CMP and niraparib, a PARP inhibitor used to treat advanced ovarian cancer, they reprogrammed the TME, leading to the influx of CD8+ T cells, the immune cells responsible for killing tumors. Notably, changes in the TME improved anti-tumor functions and enhanced the efficacy of niraparib.
The evidence that claudin-4 contributes to immune evasion and tumor survival underscores its potential as a promising target, providing strong rationale for further research and development efforts.
Sources: Sci Rep, Int J Mol Sci, Nat Revs Clinic Oncol