Promoter Demethylation Upregulates STEAP1 Gene Expression in Human Prostate Cancer: In Vitro and In Silico Analysis

Rocha, Sandra M.; Sousa, Inês; Gomes, Inês M.; Arinto, Patrícia; Costa-Pinheiro, Pedro; Coutinho, Eduarda; Santos, Cecília R. A.; Jerónimo, Carmen; Lemos, Manuel C.; Passarinha, Luís A.; Socorro, Sílvia; Maia, Cláudio J.

doi:10.3390/life11111251

Cited by 5 publications

(5 citation statements)

References 42 publications

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“…In linear correlation, negative relationships were examined between STEAP1 and several cancers such as BRCA, PRAD, SKCM, and UCEC but positive connections in COAD and LUSC. Consistent with a previous study, STEAP1 was downregulated in prostate cancer tissues compared with normal samples and negatively associated with promoter methylation levels integrating both vitro and silico analysis [38].…”

Section: Discussionsupporting

confidence: 91%

The Prognostic Value and Immunological Role of STEAP1 in Pan-Cancer: A Result of Data-Based Analysis

Zhao

Xiong

et al. 2022

Oxidative Medicine and Cellular Longevity

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Purpose. This study is aimed at systematically analyzing the expression, function, and prognostic value of six transmembrane epithelial antigen of the prostate 1 (STEAP1) in various cancers. Methods. The expressions of STEAP1 between normal and tumor tissues were analyzed using TCGA and GTEx. Clinicopathologic data was collected from GEPIA and TCGA. Prognostic analysis was conducted by Cox proportional hazard regression and Kaplan-Meier survival. DNA methylation, mutation features, and molecular subtypes of cancers were also investigated. The top-100 coexpressed genes with STEAP1 were involved in functional enrichment analysis. ESTIMATE algorithm was used to analyze the correlation between STEAP1 and immunity value. The relationships of STEAP1 and biomarkers including tumor mutational burden (TMB), microsatellite instability (MSI), and stemness score as well as chemosensitivity were also illustrated. Results. Among 33 cancers, STEAP1 was overexpressed in 19 cancers such as cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), colon adenocarcinoma, and lymphoid neoplasm diffuse large B cell lymphoma while was downregulated in 5 cancers such as adrenocortical carcinoma, breast invasive carcinoma (BRCA), and kidney chromophobe renal cell carcinoma. STEAP1 has significant prognostic relationships in multiple cancers. 15 cancers exhibited differences of DNA methylation including bladder urothelial carcinoma, BRCA, and CESC. STEAP1 expression was positively correlated to immune molecules especially in thyroid carcinoma and negatively especially in uveal melanoma. STEAP1 was associated with TMB and MSI in certain cancers. In addition, STEAP1 was connected with increased chemosensitivity of drugs such as trametinib and pimasertib. Conclusions. STEAP1 was an underlying target for prognostic prediction in different cancer types and a potential biomarker of TMB, MSI, tumor microenvironment, and chemosensitivity.

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Section: Discussionsupporting

confidence: 91%

The Prognostic Value and Immunological Role of STEAP1 in Pan-Cancer: A Result of Data-Based Analysis

Zhao

Xiong

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…However, it is unclear whether the loss of tumor STEAP1 expression is solely due to inherent tumor antigen heterogeneity or whether there is also adaptive downregulation of STEAP1 expression. A recent publication showed that promoter methylation of STEAP1 modulates STEAP1 expression and epigenetic deregulation by DNA methyltransferase and histone deacetylase inhibition was sufficient to significantly upregulate STEAP1 expression 73 . Treatment with epigenetic inhibitors in combination with STEAP1 CAR T cell therapy could simultaneously enhance tumor STEAP1 expression and reprogram CAR T cells to favorable exhaustionresistant differentiation states 74,75 , thereby mitigating tumor antigen loss and enhancing antitumor efficacy in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy

et al. 2023

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Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen for therapeutic targeting in prostate cancer. Here, we report broad expression of STEAP1 relative to prostate-specific membrane antigen (PSMA) in lethal metastatic prostate cancers and the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrate reactivity in low antigen density, antitumor activity across metastatic prostate cancer models, and safety in a human STEAP1 knock-in mouse model. STEAP1 antigen escape is a recurrent mechanism of treatment resistance and is associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein combined with STEAP1 CAR T cell therapy enhances antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading.

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“…However, it is unclear whether the loss of tumor STEAP1 expression is solely due to inherent tumor antigen heterogeneity or whether there is also adaptive downregulation of STEAP1 expression. A recent publication showed that promoter methylation of STEAP1 modulates STEAP1 expression and epigenetic deregulation by DNA methyltransferase and histone deacetylase inhibition was sufficient to significantly upregulate STEAP1 expression 57 . Perhaps treatment with epigenetic inhibitors in combination with STEAP1 CAR T cell therapy could simultaneously enhance tumor STEAP1 expression and reprogram CAR T cells to favorable exhaustion-resistant differentiation states 58, 59 , thereby mitigating tumor antigen loss and enhancing antitumor efficacy in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell therapy

Bhatia

Kamat

Pariva

et al. 2022

Preprint

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SummarySix transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling tumor-associated cell surface antigen for therapeutic targeting in solid tumors. We identified broad expression of STEAP1 (87% positive) in lethal metastatic prostate cancer, even more so than prostate-specific membrane antigen (PSMA, 60% positive) which is a clinically established diagnostic and therapeutic target. Second-generation chimeric antigen receptor (CAR) T cells were engineered for reactivity against STEAP1 and demonstrated substantial antitumor activity in metastatic human prostate cancer models in immunodeficient mice. Adoptive transfer of STEAP1 CAR T cells was associated with prolonged peripheral persistence and either disease eradication or substantial tumor growth inhibition with progressive disease demonstrating antigen loss. As STEAP1 CAR T cells were also highly active in antigen density conditions as low as ∼1,500 molecules/cell, we generated a human STEAP1 (hSTEAP1) knock-in (KI) mouse to evaluate the potential for on-target off-tumor toxicities. hSTEAP1-KI mice demonstrated a pattern of systemic hSTEAP1 expression akin to that observed in humans with the greatest expression found in the prostate gland. Mouse-in-mouse studies of STEAP1 CAR T cell therapy in immunocompetent hSTEAP1-KI mice engrafted with disseminated mouse prostate cancer showed preliminary safety without evidence of gross toxicity, cytokine storm, or architectural disruption and increased T cell infiltration at sites of systemic hSTEAP1 expression. Tumor responses and extension of survival were appreciated but antigen loss was identified in recurrent and progressive disease. In summary, we report the extent of STEAP1 expression in treatment-refractory metastatic prostate cancer, the generation of a STEAP1 CAR T cell therapy with promising potency and safety in preclinical studies of advanced prostate cancer, and antigen escape as a mechanism of resistance to effective STEAP1 CAR T cell therapy.

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Promoter Demethylation Upregulates STEAP1 Gene Expression in Human Prostate Cancer: In Vitro and In Silico Analysis

Cited by 5 publications

References 42 publications

The Prognostic Value and Immunological Role of STEAP1 in Pan-Cancer: A Result of Data-Based Analysis

The Prognostic Value and Immunological Role of STEAP1 in Pan-Cancer: A Result of Data-Based Analysis

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell therapy

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