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Page 132 Bibi et al. J Transl Genet Genom 2024;8:119-161 https://dx.doi.org/10.20517/jtgg.2023.50

However, there are certain difficulties and restrictions when using EphA2 as a potent protein for prostate
cancer immunotherapy. For instance, regarding the signaling pathway involved, EphA2 can exhibit both
tumor-promoting and tumor-suppressive properties. EphA2 acts as a tyrosine kinase, promoting tumor
growth by stimulating AKT, or functions as a pseudokinase, preventing cancer cell growth by blocking AKT
[211]
activation through ephrin-A1 stimulation . Therefore, in the development of EphA2-targeted
therapeutics, it is crucial to consider the balance between these two mechanisms of action. Moreover, the
variability in EphA2 expression and function across different prostate cancer subtypes and stages presents
another problem. In distinct prostate cancer cells, EphA2 expression levels can range from high to low, or
even be absent altogether, with its function shifting from proangiogenic to antiangiogenic as tumors
[208]
progress . This underscores the need for further research to find a more potent and effective target in
prostate cancer.

Synovial sarcoma X-chromosome breakpoint protein
The family of CTAs (cancer testis antigens) known as Synovial sarcoma X-chromosome breakpoint protein
(SSX) proteins is typically present in the testis and is abnormally expressed in various types of malignancies,
including prostate cancer . SSX1, SSX2, and SSX4 genes, involved in the typical chromosomal
[213]
translocation t (X, 18) (p11, q11) seen in synovial sarcoma, encode for SSX proteins. This translocation
results in the production of the SS18-SSX fusion protein, which is responsible for the pathogenesis of
synovial sarcoma by joining the SS18 gene (chromosome 18) to one of the SSX genes (chromosomal X) .
[214]
SSX proteins, characterized by nuclear localization and limited expression in germ cells of testis or ovary
lacking HLA class I, are frequently observed in tumors of various origins, particularly in advanced stages of
cancer, making them a superfamily of homologous CTAs [111,215] . Due to their modest expression in healthy
cells displaying HLA-class I, SSX peptides are attractive targets for T cell therapies in immunotherapy.
Recent research on PCa has revealed that while SSX protein expression is absent in primary tumors, it is
detected in a significant portion of metastatic PCa samples . Moreover, the degree of protein homology
[211]
suggests that several of the HLA class I- and II-restricted proteins represent target structures for
malignancies expressing various members of the SSX family [213-216] .

Epithelial cell adhesion molecule
Epithelial cell adhesion molecule (EpCAM) is commonly expressed in epithelial cells found in various
tissues such as the skin, gut, and prostate. In conditions like prostate cancer, there may be instances of
EpCAM overexpression or mutation, which are associated with directional growth inhibition and increased
invasiveness [217,218] . Consequently, EpCAM has been identified as a promising target for immunotherapy in
prostate cancer , a treatment strategy that harnesses the immune system to combat cancer cells.
[219]
Immunotherapy relies on targeting specific molecules present on the surface of cancer cells, such as
EpCAM, to stimulate the immune system's response against them. Various tools, including monoclonal
antibodies, immunotoxins, and small-molecule inhibitors, can be employed for this purpose [217,218] .

In both preclinical and clinical investigations, a few of these drugs have shown positive anticancer benefits.
For instance, ALW-II-41-27 (a small molecule inhibitor) binds specifically to EpCAM's ATP-binding
pocket, inhibiting its kinase function. In vitro and in vivo experiments have demonstrated that this
substance halts the growth and invasion of prostate cancer cells . Similarly, KB004, a humanized
[218]
monoclonal antibody, induces the internalization and degradation of EpCAM by recognizing an epitope in
its extracellular region. The presence of this antibody has been shown to slow down the development and
[218]
angiogenesis of prostate cancer xenografts in mice . However, utilizing EpCAM as a target for prostate