Trophoblast cell surface antigen 2 (Trop-2) has emerged as a significant focus in cancer research due to its overexpression in various malignancies, including prostate cancer. This glycoprotein, which plays a key role in tumor growth and metastasis, has shown substantial potential as a therapeutic target, particularly for treatment-resistant forms of prostate cancer. Here, we summarize recent advancements in understanding Trop-2’s role in prostate cancer and its application as a therapeutic target.

Trop-2 is a transmembrane protein that is minimally expressed in normal tissues but highly overexpressed in many cancers, including metastatic castration-resistant prostate cancer (mCRPC). Its overexpression correlates with aggressive tumor behavior, poor clinical outcomes, and resistance to standard treatments. Trop-2 is also implicated in promoting neuroendocrine differentiation—an aggressive phenotype associated with treatment resistance.
Studies have demonstrated that Trop-2 drives tumor progression by enhancing cell proliferation, survival, and metastasis. It also interacts with pathways that regulate apoptosis, such as increasing pro-apoptotic Bax expression and decreasing anti-apoptotic Bcl-2 levels.

Importantly, Trop-2 expression is linked to treatment resistance markers like AR-V7, making it a potential biomarker for advanced prostate cancer.

ADCs targeting Trop-2 represent the most advanced therapeutic approach. These agents combine monoclonal antibodies specific to Trop-2 with cytotoxic drugs, delivering targeted therapy to cancer cells while sparing normal tissues. Sacituzumab govitecan (SG) is one such ADC approved for other cancers and now being explored for prostate cancer. Preclinical studies have shown that SG’s efficacy depends on Trop-2 expression levels, highlighting its potential for personalized therapy.

Trop-2 can serve as a biomarker for isolating circulating tumor cells (CTCs) from blood samples, aiding in non-invasive diagnostics and monitoring treatment response. Its expression levels may also predict the effectiveness of ADCs, allowing for tailored treatment strategies.

Emerging evidence suggests that combining Trop-2-targeted therapies with other agents, such as PARP inhibitors or immunotherapies, could enhance efficacy. For example, PARP inhibitors have shown promise in reducing neuroendocrine features driven by Trop-2.

Despite its promise, challenges remain in optimizing Trop-2-targeted therapies. These include managing side effects of ADCs and addressing variability in Trop-2 expression across tumors. Future research aims to develop safer and more effective therapies by exploring novel epitopes on the Trop-2 protein and refining patient selection through robust biomarker strategies.

Trop-2 represents a transformative opportunity in prostate cancer treatment. Its role as both a driver of aggressive disease and a therapeutic target offers hope for patients with limited options. As research progresses, Trop-2-targeted therapies are poised to become an integral part of precision oncology for prostate cancer.