EZH2 inhibitor Combined With PD-1 inhibitor, Enhance The Therapeutic Effect of Prostate Cancer Huateng

Huateng Pharma https://en.huatengsci.com

EZH2 inhibitor Combined With PD-1 inhibitor, Enhance

The Therapeutic Effect of Prostate Cancer

Prostate cancer is cancer that occurs in the prostate. It is the most common cancer
among men (after skin cancer). Unfortunately, metastatic castration-resistant prostate
cancer (mCRPC) is still incurable. Although immune checkpoint therapy can produce a
significant response in 15-20% of prostate cancer patients, it is only effective in about 5%
of prostate cancer patients. The resistance of prostate cancer patients to immune
checkpoint therapy is believed to be related to low tumor immunogenicity and
immunosuppressive tumor microenvironment.

EZH2 is a hot target in the field of epigenetic anti-tumor research in recent
years. Increased expression and activity of EZH2 are important factors in the
occurrence and development of prostate cancer. Tumors with enhanced EZH2
function often show immunosuppressive tumor microenvironment and immunotherapy
resistance. However, the epigenetic mechanism of EZH2-mediated prostate cancer
resistance to immune checkpoint therapy has not been confirmed.

On March 22, 2021, researchers from the Dana-Farber Cancer Institute in the United
States published a research paper in Nature Cancer titled: EZH2 inhibition activates a
dsRNA–STING–interferon stress axis that potentiates response to PD-1 checkpoint
blockade in prostate cancer.

Huateng Pharma https://en.huatengsci.com

The study shows that inhibiting EZH2 can reduce prostate cancer resistance to
immune checkpoint therapy. It is suggested that the combination therapy of EZH2
inhibitor + immune checkpoint inhibitor can increase the effect of immunotherapy for
prostate cancer and can be used as a promising treatment plan.

In this study, the research team investigated the effect of EZH2 function loss on prostate
cancer cell activation and PD-1 treatment resistance to determine the epigenetic
mechanism of EZH2-mediated prostate cancer resistance to immune checkpoint therapy.

The research team used three-dimensional tumor-like organs extracted from a genetically
engineered prostate cancer mouse model (GEMM) expressing oncogenes CMYC, EZH2
alleles, and a prostate-specific antigen (PSA) promoter that induces Cre recombinase
(EMC mice). It is found that EZH2 negatively regulates type I/II interferon-stimulating
genes (ISG) in prostate cancer through RNA seq and ImageStream flow cytometry.

In order to further understand the potential mechanism of EZH2 inhibiting ISG, the
research team used publicly published chromatin immunoprecipitation (ChIP) data sets of
prostate cancer patients and cell lines, genetic mice and cell lines to prove the inner
hospital retrovirus sequences (ERVs) Directly down-regulating the activation of ISGs after
EZH2 inhibition and STING are essential for up-regulating the anti-cancer immunogenicity
of EZH2 inhibition.

Huateng Pharma https://en.huatengsci.com

In order to further understand the potential mechanism of EZH2 inhibiting ISG, the
research team used publicly published chromatin immunoprecipitation (ChIP) data sets of
prostate cancer patients and cell lines, genetic mice and cell lines to prove endogenous
retroviral sequences (ERVs) directly down-regulate the activation of ISGs after EZH2
inhibition and STING are critical for up-regulation of anti-tumor immunogenicity against
EZH2 inhibition.

Next, the research team used the B6-HiMYC-PCa transgenic tissue transplantation
mouse model and found that EZH2 inhibition or PD-1 treatment alone did not show
anti-tumor activity, but the combination therapy showed significant therapeutic
effects. In vitro cytotoxicity tests proved that the inhibition of EZH2 activity leads to a
significant loss of immune-mediated cytotoxicity, which depends on the up-regulation of
tumor cell PD-L1.

Huateng Pharma https://en.huatengsci.com

In general, chemical or genetic inhibition of EZH2 in tumor cells will inhibit endogenous
dsRNA in the cell, resulting in enhanced STING-ISG response, immune cell activation and
sensitivity to PD-1 blockade. These findings provide substantial insights into the
immunotherapy of prostate cancer, and provide a theoretical basis for the development of
EZH2 inhibitors as a therapeutic strategy to enhance the response of prostate cancer to
immune checkpoint immunotherapy.

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Reference: EZH2 inhibition activates a dsRNA–STING–interferon stress axis that potentiates response
to PD-1 checkpoint blockade in prostate cancer