PRAME: Biomarker and Therapeutic Target in multiple Malignancies
Classification & Expression
PRAME is a cancer-testis antigen (CTA) encoded on chromosome 22, among several genes for immunoglobulin proteins. It is normally expressed in testis, ovary, placenta, and at low levels in adrenal and endometrial tissues.
While it is not expressed in most adult tissues, it is overexpressed in many malignancies:
- Cutaneous and uveal melanoma
- Non-melanoma skin cancer
- Merkel cell carcinoma
- Leukaemia; Acute Myeloid Leukaemia
- Breast and ovarian cancer
- Non-small cell lung cancer (NSCLC)
- Neuroblastoma
This restricted expression profile makes PRAME a prime target for T-cell–based immunotherapy.
Biological Functions in Tumorigenesis
PRAME contributes to tumor development via multiple mechanisms:
- Represses retinoic acid signaling, blocking differentiation and promoting proliferation.
- Promotes epithelial-to-mesenchymal transition (EMT), a process in which cells lose their adhesion to neighboring cells, increase their motility and gain migration potential.
- Contributes to the formation of an immunosuppressive (“cold”) tumor microenvironment, via increased checkpoint expression and reduced antigen presentation.
Diagnostic & Prognostic Utility
- PRAME is often strongly expressed in primary and metastatic melanomas but absent or weakly expressed in benign nevi, making it a highly sensitive (>90%) and specific marker for melanocytic lesions.
- An increased expression of PRAME is associated with a poorer prognosis in melanomas and other malignancies.
- In hematologic malignancies the prognostic impact is mixed: PRAME overexpression is linked to poor prognosis in diffuse large B-cell lymphoma, Hodgkin’s lymphoma, multiple myeloma, and chronic leukemia. However, in pediatric B-cell acute lymphoblastic leukemia, higher PRAME levels have been associated with better outcomes.
Challenges & Innovative Strategies
Challenge |
Strategy |
| Tumor heterogeneity |
Use of demethylating agents to upregulate PRAME artificially |
| Cold tumor microenvironment |
Combos of cancer vaccines and checkpoint inhibitors (e.g., nivolumab, ipilimumab) |
| Downregulation of HLA-I molecules |
Co-treatment with MEK inhibitors or epigenetic drugs to restore antigen presentation |
Summary
PRAME is a versatile biomarker and therapeutic target due to its selective tumor expression, functional roles in malignancy, and emerging clinical applications. Current efforts focus on overcoming immune evasion and tumor heterogeneity through combination therapies and epigenetic modulation, positioning PRAME at the forefront of precision immuno-oncology.
Literature
- Cassalia, Fortunato et al. “PRAME Updated: Diagnostic, Prognostic, and Therapeutic Role in Skin Cancer.” International journal of molecular sciences vol. 25,3 1582. 27 Jan. 2024, doi:10.3390/ijms25031582
- Blount SL, Liu X, McBride JD. The Utilization of PRAME in the Diagnosis, Prognosis, and Treatment of Melanoma. Cells. 2024 Oct 20;13(20):1740. doi: 10.3390/cells13201740. PMID: 39451258; PMCID: PMC11505691.