Overexpression and surface localization of HPRT in prostate cancer provides a potential target for cancer specific antibody mediated cellular cytotoxicity

Townsend, Michelle H.; Bennion, Kelsey B.; Bitter, Eliza E.; Felsted, Abigail M.; Robison, Richard A.; O’Neill, Kim L.

doi:10.1016/j.yexcr.2021.112567

Cited by 9 publications

(9 citation statements)

References 21 publications

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“…Inhibitors for DGKA can exhibit antitumor e cacy in different tumorbearing animal models. Similarly, inhibitors for HPRT1 have been proven to be potential therapeutic targets in prostate cancer and gastrointestinal tumors [12,13]. ADRB1 has been reported to be related to immunotherapy for breast cancer [14], high expression of ADRB1 predicts a better prognosis.…”

Section: Discussionmentioning

confidence: 99%

Establishment and validation of a prognostic signature for lung squamous cell carcinoma based on metabolism‐related genes

Yan

Guo

et al. 2023

Preprint

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Background Lung squamous cell carcinoma (LUSC) is a main subgroup of non-small cell lung cancer that accounts for ~ approximately 80% of all lung cancer. Studies have demonstrated that tumor microenvironment is essential for the occurrence and development of LUSC. The present study identified the immune- and metabolic-related genes to construct a prognostic model for LUSC patients. Methods We downloaded RNA-sequence data and clinical information of LUSC patients from The Cancer Genome Atlas database. The differentially expressed metabolic-related genes (DMRGs) and the differentially expressed immune-related genes (DIRGs) between the control samples and LUSC patient samples were identified. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes analysis were performed to explore the potential biological processes of harvested DMRGs and DIRGs. To develop a prognostic model for LUSC patients, we selected prognostic genes from DMRGs and DIRGs through the univariate and multivariate Cox regression. The prognostic value of the risk model was detected via the Kaplan-Meier curve and the area under the receiver operating characteristic curve analysis. Gene set enrichment analysis (GSEA) was operated to investigate the underlying latent pathways associated with the high-risk group. The infiltration of immune cells in the high- and low-risk groups were analyzed using the single-sample gene-set enrichment analysis. Results A total of 178 DMRGs were identified, which were mainly enriched in nucleoside phosphate biosynthetic process, carboxylic acid biosynthetic process, and cofactor metabolic process. Around 264 DIRGs were primarily associated with chemotaxis regulation, leukocyte migration, and positive regulation of cytokine production. After the univariate and multivariate Cox regression analyses, a prognostic risk model containing four prognostic genes was constructed, which performed better in prognosing LUSC patients via the ROC analysis. Moreover, the risk score was found to be an independent prognostic factor through the multivariate Cox regressions analysis. The GSEA suggested that the chemokine signaling pathway, cytokine-cytokine receptor interaction, and IL-17 signaling pathway were mainly enriched in the high-risk group. Finally, the risk score was mostly correlated with immune-related score and immune infiltration cells. Conclusion We constructed an immune- and metabolic-related gene signature that was quite reliable in predicting prognosis of LUSC patients.

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Section: Discussionmentioning

confidence: 99%

Establishment and validation of a prognostic signature for lung squamous cell carcinoma based on metabolism‐related genes

Yan

Guo

et al. 2023

Preprint

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“…Literature data reported controversial results regarding this biomarker, but recently published studies highlighted that it is not a suitable control for cancer-related experiments as it exhibits expression variability when comparing normal to malignant samples [ 35 ]. Moreover, HPRT1 has a higher statistically significant expression on prostate cancer cells and is significantly upregulated in a large proportion of prostate cancer tissue samples [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating tumor cell gene expression and plasma AR gene copy number as biomarkers for castration-resistant prostate cancer patients treated with cabazitaxel

Gurioli

Conteduca

Brighi

et al. 2022

BMC Med

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Background Cabazitaxel improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients progressing after docetaxel. In this prospective study, we evaluated the prognostic role of CTC gene expression on cabazitaxel-treated patients and its association with plasma androgen receptor (AR) copy number (CN). Methods Patients receiving cabazitaxel 20 or 25 mg/sqm for mCRPC were enrolled. Digital PCR was performed to assess plasma AR CN status. CTC enrichment was assessed using the AdnaTest EMT-2/StemCell kit. CTC expression analyses were performed for 17 genes. Data are expressed as hazard ratio (HR) or odds ratio (OR) and 95% CI. Results Seventy-four patients were fully evaluable. CTC expression of AR-V7 (HR=2.52, 1.24–5.12, p=0.011), AKR1C3 (HR=2.01, 1.06–3.81, p=0.031), AR (HR=2.70, 1.46–5.01, p=0.002), EPCAM (HR=3.75, 2.10–6.71, p< 0.0001), PSMA (HR=2.09, 1.19–3.66, p=0.01), MDK (HR=3.35, 1.83–6.13, p< 0.0001), and HPRT1 (HR=2.46, 1.44–4.18, p=0.0009) was significantly associated with OS. ALDH1 (OR=5.50, 0.97–31.22, p=0.05), AR (OR=8.71, 2.32–32.25, p=0.001), EPCAM (OR=7.26, 1.47–35.73, p=0.015), PSMA (OR=3.86, 1.10–13.50, p=0.035), MDK (OR=6.84, 1.87–24.98, p=0.004), and HPRT1 (OR=7.41, 1.82–30.19, p=0.005) expression was associated with early PD. AR CN status was significantly correlated with AR-V7 (p=0.05), EPCAM (p=0.02), and MDK (p=0.002) expression. In multivariable model, EPCAM and HPRT1 CTC expression, plasma AR CN gain, ECOG PS=2, and liver metastases and PSA were independently associated with poorer OS. In patients treated with cabazitaxel 20 mg/sqm, median OS was shorter in AR-V7 positive than negative patients (6.6 versus 14 months, HR=3.46, 1.47–8.17], p=0.004). Conclusions Baseline CTC biomarkers may be prognosticators for cabazitaxel-treated mCRPC patients. Cabazitaxel at lower (20 mg/sqm) dose was associated with poorer outcomes in AR-V7 positive patients compared to AR-V7 negative patients in a post hoc subgroup analysis. Trial registration Clinicaltrials.govNCT03381326. Retrospectively registered on 18 December 2017.

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“…Moreover, it is also important to point out that other nucleotide salvage pathway enzymes have been reported to be localized on the cell membrane e.g., hypoxanthine-phosphoribosyl transferase (HPRT). Targeting of this enzyme with monoclonal antibodies has also been recently reported [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Selection of human single domain antibodies (sdAb) against thymidine kinase 1 and their incorporation into sdAb-Fc antibody constructs for potential use in cancer therapy

et al. 2022

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Thymidine Kinase 1 (TK1) is primarily known as a cancer biomarker with good prognostic capabilities for both hematological and solid malignancies. However, recent studies targeting TK1 at protein and mRNA levels have shown that TK1 may be useful as a therapeutic target. In order to examine the use of TK1 as a therapeutic target, it is necessary to develop therapeutics specific for it. Single domain antibodies (sdAbs), represent an exciting approach for the development of immunotherapeutics due to their cost-effective production and higher tumor penetration than conventional antibodies. In this study, we isolated sdAb fragments specific to human TK1 from a human sdAb library. A total of 400 sdAbs were screened through 5 rounds of selection by monoclonal phage ELISA. The most sensitive sdAb fragments were selected as candidates for preclinical testing. The sdAb fragments showed specificity for human TK1 in phage ELISA, Western blot analysis and had an estimated limit of detection of 3.9 ng/ml for the antibody fragments 4-H-TK1_A1 and 4-H-TK1_D1. The antibody fragments were successfully expressed and used for detection of membrane associated TK1 (mTK1) through flow cytometry on cancer cells [lung (~95%), colon (~87%), breast (~53%)] and healthy human mononuclear cells (MNC). The most sensitive antibody fragments, 4-H-TK1_A1 and 4-H-TK1_D1 were fused to an engineered IgG1 Fc fragment. When added to cancer cells expressing mTK1 co-cultured with human MNCs, the anti-TK1-sdAb-IgG1_A1 and D1 were able to elicit a significant antibody-dependent cell-mediated cytotoxicity (ADCC) response against lung cancer cells compared to isotype controls (P<0.0267 and P<0.0265, respectively). To our knowledge this is the first time that the isolation and evaluation of human anti-TK1 single domain antibodies using phage display technology has been reported. The antibody fragments isolated here may represent a valuable resource for the detection and the targeting of TK1 on tumor cells.

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Overexpression and surface localization of HPRT in prostate cancer provides a potential target for cancer specific antibody mediated cellular cytotoxicity

Cited by 9 publications

References 21 publications

Establishment and validation of a prognostic signature for lung squamous cell carcinoma based on metabolism‐related genes

Establishment and validation of a prognostic signature for lung squamous cell carcinoma based on metabolism‐related genes

Circulating tumor cell gene expression and plasma AR gene copy number as biomarkers for castration-resistant prostate cancer patients treated with cabazitaxel

Selection of human single domain antibodies (sdAb) against thymidine kinase 1 and their incorporation into sdAb-Fc antibody constructs for potential use in cancer therapy

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