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Bibi et al. J Transl Genet Genom 2024;8:119-161 https://dx.doi.org/10.20517/jtgg.2023.50 Page 131

A significant proportion of PCa cases exhibited elevated EGFR levels, which has been associated with the
progression of PCa towards androgen independence. In vivo trials administering EGFR-specific monoclonal
antibodies cetuximab and panitumumab have demonstrated the suppression of cancer development in
multiple prostate cancer xenograft models [111,200] . Despite EGFR primarily being investigated as a target for
monoclonal antibodies, several CTL epitopes have been found [111,201] . Moreover, HER4 has emerged as a
potential target molecule in prostate cancer research. Both mouse xenograft models and In vitro studies
have shown that HER 4 antibodies effectively slow the development of various types of prostate cancer.
Additionally, concomitant radiation therapy may enhance the efficacy of HER 4-directed monoclonal
antibody treatment [111,202] .

HER 2/neu, EGFR, and HER-4 are prospective targets for immunotherapy in prostate cancer. However,
their precise functions and effectiveness are still under investigation. Various factors, such as tumor
heterogeneity, receptor dimerization, ligand availability, signaling crosstalk, immune evasion, and genetic
changes, may affect both the responsiveness and resistance to targeting these receptors in prostate cancer.
Therefore, further study is required to refine patient selection, therapy combination, and outcome
monitoring in prostate cancer immunotherapy targeting the HER family.

N-Cadherin
N-cadherin, a protein integral to cell adhesion and migration, plays a pivotal role in various aspects of
tumor progression, including the facilitation of epithelial-mesenchymal transition and the augmentation of
cell movement rate. Its upregulation is a hallmark of tumor invasiveness and metastasis formation, such as
pelvic lymph node infiltration and bone metastases in PCa [203,204] . Furthermore, in PCa, N-cadherin
overexpression has been linked to de-differentiation, androgen deprivation, and the shift to androgen
independence. Efforts to target castration-resistant PCa using mAbs have yielded promising results,
significantly slowing the development of such xenografts, inhibiting invasion and metastasis, and delaying
the development of androgen resistance [205,206] . Given its crucial role in tumor survival and resistance, N-
cadherin emerges as a special target for prostate cancer immunotherapy. Consequently, numerous
immunotherapeutic strategies have been devised or are currently under investigation to specifically target
N-cadherin in prostate cancer. Although several of these methods have demonstrated encouraging results in
clinical trials, they are not devoid of difficulties and restrictions. To maximize the effectiveness and safety of
various therapies and to identify the most suitable patients for each treatment modality, more study is
required.

Erythropoietin producing hepatocellular receptor tyrosine kinase class A2
Erythropoietin producing hepatocellular receptor tyrosine kinase class A2 (EphA2), a cell membrane-
attached receptor with tyrosine kinase activity, is expressed in a wide variety of normal tissues and is notably
overexpressed in numerous epithelial malignancies, including prostate cancer [203-207] . In advanced PCa,
EphA2 shows promise as a potent molecule for both active and passive immunotherapy. Various HLA class
I- and II-restricted proteins have been discovered, and when pulsed onto DCs, some of these peptides
exhibited antitumor effects in mice models .
[111]

Extensive investigation into the immune-therapeutical potential of monoclonal antibodies targeting EphA2
was conducted using preclinical in vivo models. These antibodies, by effectively downregulating EphA2 on
the cell surface [208,209] , induce receptor internalization and disruption. Additionally, by decreasing tumor cell
proliferation, promoting apoptotic activity, and reducing microvascular density, they exhibit robust
antitumor effects when used alone or in combination with chemotherapy in a variety of xenograft
models [111,210,211] . Cytotoxic immune-conjugates offer a highly effective way to target tumors because they
quickly internalize receptors when an agonistic antibody targets them [111,212] .