Junguo Chen, Yanhong Zhang, Xijie Chen, Dandong Luo, Danlin Liu, Zhaoliang Yu, Yanyun Lin, Xiaosheng He, Juanni Huang, Lei Lian
{"title":"Raddeanin A Inhibits Colorectal Cancer Growth and Ameliorates Oxaliplatin Resistance Through the WNT/β-Catenin Signaling Pathway.","authors":"Junguo Chen, Yanhong Zhang, Xijie Chen, Dandong Luo, Danlin Liu, Zhaoliang Yu, Yanyun Lin, Xiaosheng He, Juanni Huang, Lei Lian","doi":"10.1089/cbr.2024.0061","DOIUrl":"10.1089/cbr.2024.0061","url":null,"abstract":"<p><p><b><i>Background:</i></b> Chemotherapy based on oxaliplatin (OXA) is the first-line treatment for advanced colorectal cancer (CRC), and acquired resistance to OXA is the main reason for clinical treatment failure in CRC. <b><i>Methods:</i></b> To search for compounds that can reverse OXA resistance, we screened a small molecule inhibitor drug library and identified a drug, Raddeanin A (RA), that enhanced the anticancer effect of OXA. Using human CRC cell lines, CRC organoid models, and <i>in vivo</i> subcutaneous tumorigenic studies, we determined that RA inhibits the proliferation of CRC cells by promoting apoptosis and inducing cell cycle arrest. <b><i>Results:</i></b> We constructed OXA-resistant CRC cell lines and demonstrated that RA enhances the sensitivity of these cells to OXA. Further experiments showed that the mechanism by which RA enhanced the anticancer effects of OXA in CRC was by inhibiting the activation of the WNT/β-catenin signaling pathway. <b><i>Conclusions:</i></b> Because RA has been shown to be biocompatible in animal models, there is a possibility that RA could be developed as a sensitizer for resistant cancer cells or as a novel lead compound to enhance the therapeutic efficacy of OXA in resistant CRCs.</p>","PeriodicalId":55277,"journal":{"name":"Cancer Biotherapy and Radiopharmaceuticals","volume":" ","pages":"41-53"},"PeriodicalIF":2.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"<i>SERPINH1</i> as a Novel Biomarker for Colon Cancer Bone Metastasis with Machine Learning and Immunohistochemistry Validation.","authors":"Guoping Zhao, Tianjun Song, Qingfa Qing, Huaifu Cheng, Jinmin Zhao","doi":"10.1089/cbr.2024.0162","DOIUrl":"10.1089/cbr.2024.0162","url":null,"abstract":"<p><p><b><i>Background:</i></b> Bone metastasis (BM) is a serious clinical symptom of advanced colorectal cancer. However, there is a lack of effective biomarkers for early diagnosis and treatment. <b><i>Method:</i></b> RNA-seq data from public databases (GSE49355, GSE101607) were collected and normalized and batch effects were removed using the combat package. Differential expression analysis was performed to identify significant genes. Robust Rank Aggregation and machine learning algorithms were used to pinpoint candidate biomarkers. These biomarkers were validated using immunohistochemistry and further analyzed for survival rates. Enrichment analysis was conducted to explore biological mechanisms. Additionally, drug sensitivity and immune infiltration analyses were performed to provide insights into potential therapeutic targets. <b><i>Results:</i></b> Analysis results revealed 386 genes elevated in primary versus normal tissues and 26 genes varying between primary and BM. Serpin Protease Inhibitor Clade H1 (<i>SERPINH1)</i> as a novel biomarker for colon cancer metastasis. High <i>SERPINH1</i> expression correlates with poor survival outcomes and is linked to high lymphatic invasion and advanced cancer stages. Additionally, <i>SERPINH1</i> expression influences immune infiltration and is not predictive of chemotherapy response, but potential new drugs are suggested for high-expression cases. The gene also enriches classical cancer pathways such as Hedgehog and transforming growth factor-β. <b><i>Conclusions:</i></b> We identified novel colon cancer BM markers, including <i>SERPINH1</i>, using machine learning algorithms combined with traditional transcriptomic data and validated their expression through immunohistochemistry. This biomarker could significantly assist clinicians in making more precise treatment decisions.</p>","PeriodicalId":55277,"journal":{"name":"Cancer Biotherapy and Radiopharmaceuticals","volume":" ","pages":"31-40"},"PeriodicalIF":2.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142481429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qin Li, Bin Chen, Luz Angela Torres-de la Roche, Zimo Gong, Guilin Wang, Rui Zhuo, Rudy Leon De Wilde, Xiaopeng Chen, Wanwan Wang
{"title":"Ultrasound Genomics Reveals a Signature for Predicting Breast Cancer Prognosis and Therapy Response.","authors":"Qin Li, Bin Chen, Luz Angela Torres-de la Roche, Zimo Gong, Guilin Wang, Rui Zhuo, Rudy Leon De Wilde, Xiaopeng Chen, Wanwan Wang","doi":"10.1089/cbr.2024.0127","DOIUrl":"10.1089/cbr.2024.0127","url":null,"abstract":"<p><p><b><i>Background:</i></b> Breast cancer (BC) in women is the most common malignancy worldwide, but there is still a lack of validated tools to accurately assess patient prognosis and response to available chemotherapy treatment regimens. <b><i>Method:</i></b> We collected ultrasound images and transcriptome data of BC from our breast center and public database. Key ultrasound features were then identified by using the support vector machine (SVM) algorithm and correlated with prognostic genes. Long-term survival-related genes were identified through differential expression analysis, and a prognostic evaluation model was established by using Cox regression. In addition, <i>VPS28</i> from the model was identified as a promising biomarker for BC. <b><i>Results:</i></b> Using univariate logistic regression and SVM algorithms, we identified 12 ultrasound features significantly associated with chemotherapy response. Subsequent correlation and differential expression analyses linked 401 genes to these features, from which five key signature genes were derived using Lasso and multivariate Cox regression models. This signature not only facilitates the stratification of patients into risk-specific treatment pathways but also predicts their chemotherapy response, thus supporting personalized medicine in clinical settings. Notably, <i>VPS28</i>, in the signature, emerged as a significant biomarker, strongly associated with poor prognosis, greater tumor invasiveness, and differing expression across demographic groups. <b><i>Conclusion:</i></b> In this study, we use ultrasound genomics to reveal a signature that can provide an effective tool for prognostic assessment and predicting chemotherapy response in patients with BC.</p>","PeriodicalId":55277,"journal":{"name":"Cancer Biotherapy and Radiopharmaceuticals","volume":" ","pages":"54-61"},"PeriodicalIF":2.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142309181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yiping Xu, Yurong Cai, Youyuan Deng, Ye He, Juan Wu, Shunqiu Chang, Xuebo Yan, Jianguo Wang
{"title":"RAC2 as a Tumor-Suppressive Biomarker Associated with T Cell Infiltration in Breast Cancer.","authors":"Yiping Xu, Yurong Cai, Youyuan Deng, Ye He, Juan Wu, Shunqiu Chang, Xuebo Yan, Jianguo Wang","doi":"10.1089/cbr.2024.0142","DOIUrl":"10.1089/cbr.2024.0142","url":null,"abstract":"<p><p><b><i>Background:</i></b> RAC2 is critical in regulating the homeostasis of hematopoietic stem cells. Nonetheless, its role in breast cancer (BC) remains unclear, necessitating further investigation. <b><i>Methods:</i></b> The expression of RAC2 in BC and healthy tissues was acquired from The Cancer Genome Atlas. Its validity was further assessed using datasets from the gene expression omnibus database. The Tumor Immune Single-cell Hub database was used to collect and analyze the single-cell RNA sequencing datasets of BC. The diagnostic relevance of RAC2 was evaluated using receiver operating characteristic curves. Further assessment was carried out via enrichment analyses; Gene Set Analysis, immune scoring, single-cell sequencing, and immunohistochemical analysis were conducted to confirm the relationship between RAC2 expression and immune infiltration. <b><i>Results:</i></b> RAC2 expression was notably heightened in BC (<i>p</i> < 0.001). It was observed that a better prognosis was linked to heightened expression of RAC2 (<i>p</i> < 0.01), with the diagnostic efficacy of the marker noted to be good (area under the curve = 0.858). We found a lower percentage of protumor immune cells and a greater proportion of antitumor immune cells in the high RAC2. Our analysis revealed alterations in gene expression and an enriched network of immune pathways influenced by RAC2. Notably, cytotoxic genes, chemokines, chemokine receptors, immunostimulators, and immunosuppressive molecules positively correlated with RAC2 expression. RAC2 expression reliably predicted how patients would respond to two different therapeutic approaches in BC. <b><i>Conclusions:</i></b> The RAC2 was found to be a key biomarker in BC in the current study, demonstrating considerable potential as a prognostic and diagnostic marker. These results highlight the RAC2 potential to improve precision medicine strategies and treatment outcomes for patients with BC.</p>","PeriodicalId":55277,"journal":{"name":"Cancer Biotherapy and Radiopharmaceuticals","volume":" ","pages":"62-77"},"PeriodicalIF":2.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"<i>WT1</i> and <i>DNMT3A</i> Mutations in Prognostic Significance of Acute Myeloid Leukemia: A Meta-Analysis.","authors":"Shiyue Ma, Lingjian Tang, Hui Tang, Chaoli Wu, Xue Pu, Jun Yang, Ninhong Niu","doi":"10.1089/cbr.2024.0093","DOIUrl":"10.1089/cbr.2024.0093","url":null,"abstract":"<p><p><b><i>Background:</i></b> Adult acute leukemia most commonly manifests as acute myeloid leukemia (AML), a highly heterogeneous malignant tumor of the blood system. The application of genetic diagnostic technology is currently prevalent in numerous clinical sectors. According to recent research, the presence of specific gene mutations or rearrangements in leukemia cells is the primary cause of the disease. As different types of leukemia are caused by atypical mutated genes, testing for these mutations or rearrangements can help diagnose leukemia and identify the disease's molecular targets for treatment. <b><i>Methods:</i></b> Using the search fields \"<i>WT1</i>,\" \"<i>DNMT3A</i>,\" \"Acute myeloid leukemia,\" and \"survival,\" the CBM, Cochrane Library, Scopus, EMBASE, and PUBMED databases were separately reviewed. The methodology for evaluating the risk of bias developed by the Cochrane Collaboration was used in conjunction with a methodical evaluation of pertinent literature. Excluded studies with the following characteristics: (1) incomplete and repetitive publications, (2) unable to retrieve or convert data, (3) non-English or Chinese articles. <b><i>Results:</i></b> This analysis included 13 studies covering a total of 3478 subjects. The frequency of Wilms' Tumor 1 (<i>WT1</i>) mutations is 6.7%-35.73%, and the frequency of <i>DNMT3A</i> mutations is 12.06%-51.1%. The remission rate of patients with <i>WT1</i> mutations was less than that of patients without <i>WT1</i> mutations (OR = 0.22; 95% confidence interval [CI]: 0.14, 0.36; <i>p</i> < 0.00001; <i>I</i><sup>2</sup> = 55%). The <i>DNMT3A</i> mutation has no statistical significance for the prognosis of AML (OR = 1.21; 95% CI: 0.93, 1.58; <i>p</i> = 0.16; <i>I</i><sup>2</sup> = 80%). After removing one study, the heterogeneity of the indicator (mitigation rate) among other studies of <i>DNMT3A</i> mutation was dramatically reduced (OR = 0.63; 95% CI: 0.43, 0.93; <i>p</i> = 0.02; <i>I</i><sup>2</sup> = 0%). <b><i>Conclusions:</i></b> Our meta-analysis shows that <i>WT1</i> mutations hurt the remission rate of AML. Moreover, the impact of <i>DNMT3A</i> mutations on AML needs to be treated with caution. Gene diagnosis is critical for the prognosis and clinical management of AML.</p>","PeriodicalId":55277,"journal":{"name":"Cancer Biotherapy and Radiopharmaceuticals","volume":" ","pages":"22-30"},"PeriodicalIF":2.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Haijiao Yan, Qian Deng, Yu Meng, Ye Zhang, Jun Wu, Wensong Liu
{"title":"IL-21 and IL-33 May Be Effective Biomarkers to Predict the Efficacy of PD-1 Monoclonal Antibody for Advanced Cholangiocarcinoma.","authors":"Haijiao Yan, Qian Deng, Yu Meng, Ye Zhang, Jun Wu, Wensong Liu","doi":"10.1089/cbr.2024.0149","DOIUrl":"10.1089/cbr.2024.0149","url":null,"abstract":"<p><p><b><i>Background and Objective:</i></b> Treatment options for patients with advanced biliary tract cancer (BTC) are limited. The programmed cell death protein-1 (PD-1) inhibitors may have synergistic effects with chemotherapy. Therefore, the aim of our study was to provide real-world data on treatment outcomes in BTC patients receiving chemotherapy alone versus a combination of chemotherapy and PD-1 inhibitors. Additionally, we explored potential markers predictive of PD-1 inhibitor efficacy in this combined therapy. <b><i>Methods:</i></b> We conducted a review of patients at Changzhou First People's Hospital who received PD-1 inhibitors in combination with chemotherapy or chemotherapy alone as first-line treatment for advanced BTC. The primary endpoints of the study were progression-free survival (PFS) and overall survival (OS). Kaplan-Meier survival curves and the log-rank test were used to analyze the data. Immunohistochemistry showed the expression of interleukin-21 (IL-21), interleukin-33 (IL-33), and Eomes in the tumor tissue of patients who received PD-1 inhibitors in combination with chemotherapy. <b><i>Results:</i></b> The study enrolled 61 patients receiving PD-1 inhibitors combined with chemotherapy and 65 receiving chemotherapy alone. The median OS and PFS for patients receiving PD-1 inhibitors in combination with chemotherapy were 11.7 and 6.7 months, respectively. These durations were significantly longer than those for chemotherapy alone: OS of 10.3 months (95% CI: 0.16-0.21, <i>p</i> = 0.031) and PFS of 5.3 months (95% Confidence interval (CI) 0.25-0.32, <i>p</i> = 0.018). High IL-21 expression or low IL-33 expression in tumor tissue correlated with better response rates to chemotherapy combined with PD-1 inhibitors. <b><i>Conclusions:</i></b> Combining PD-1 inhibitors with chemotherapy shows good antitumor activity, making it an effective way to treat BTC. The expression profiles of IL-21 and IL-33 hold promise as potential markers for guiding the chemotherapy combined with immunotherapy in BTC patients.</p>","PeriodicalId":55277,"journal":{"name":"Cancer Biotherapy and Radiopharmaceuticals","volume":" ","pages":"78-88"},"PeriodicalIF":2.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Human Biodistribution and Radiation Dosimetry of the Targeting Fibroblast Growth Factor Receptor 1-Positive Tumors Tracer [<sup>68</sup>Ga]Ga-DOTA-FGFR1-Peptide.","authors":"Huiqing Yuan, Xiaoshan Chen, Mengmeng Zhao, Xinming Zhao, Xiaolin Chen, Jingya Han, Zhaoqi Zhang, Jingmian Zhang, Jianfang Wang, Meng Dai, Yunuan Liu","doi":"10.1089/cbr.2024.0073","DOIUrl":"10.1089/cbr.2024.0073","url":null,"abstract":"<p><p><b><i>Objective:</i></b> [<sup>68</sup>Ga]Ga-DOTA-FGFR1-peptide is a novel positron emission tomography (PET) radiotracer targeting fibroblast growth factor receptor 1 (FGFR1). This study evaluated the safety, biodistribution, radiation dosimetry, and imaging potential of [<sup>68</sup>Ga]Ga-DOTA-FGFR1-peptide. <b><i>Methods:</i></b> The FGFR1-targeting peptide DOTA-(PEG2)-KAEWKSLGEEAWHSK was synthesized by manual solid-phase peptide synthesis with high-performance liquid chromatography purification, and labeled with <sup>68</sup>Ga with DOTA as chelating agent. We recruited 14 participants and calculated the radiation dose of 4 of these pathologically confirmed nontumor subjects using OLINDA/EXM 2.2.0 software. At the same time, the imaging potential in 10 of these lung cancer patients was evaluated. <b><i>Results:</i></b> The biodistribution of [<sup>68</sup>Ga]Ga-DOTA-FGFR1-peptide in 4 subjects showed the highest uptake in the bladder and kidney. Dosimetry analysis indicated that the bladder wall received the highest effective dose (3.73E-02 mSv/MBq), followed by the lungs (2.36E-03 mSv/MBq) and red bone marrow (2.09E-03 mSv/MBq). No normal organs were found to have excess specific absorbed doses. The average systemic effective dose was 4.97E-02 mSv/MBq. The primary and metastatic tumor lesions were clearly visible on PET/computed tomography (CT) images in 10 patients. <b><i>Conclusion:</i></b> Our results indicate that [<sup>68</sup>Ga]Ga-DOTA-FGFR1-peptide has a good dosimetry profile and can be used safely in humans, and it has significant potential value for clinical PET/CT imaging.</p>","PeriodicalId":55277,"journal":{"name":"Cancer Biotherapy and Radiopharmaceuticals","volume":" ","pages":"712-720"},"PeriodicalIF":2.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141635862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"GRHPR, Targeted by miR-138-5p, Inhibits the Proliferation and Metastasis of Hepatocellular Carcinoma Through PI3K/AKT Signaling Pathway.","authors":"Shuangshuang Yang, Yixian Liu, Bushi Zhang, Jinxia Li, Fang Xu, Mengdan Yu, Ying Chen, Chenglong Li, Ting Liu, Ying Zhao, Qianwei Zhao, Jintao Zhang","doi":"10.1089/cbr.2023.0018","DOIUrl":"10.1089/cbr.2023.0018","url":null,"abstract":"<p><p><b><i>Background:</i></b> Hepatocellular carcinoma (HCC) is a highly aggressive cancer. This study elucidates the role of Glyoxylate reductase/hydroxypyruvate reductase (GRHPR) in HCC proliferation and metastasis, along with its molecular mechanism, and identifies miRNAs targeting GRHPR. <b><i>Materials and Methods:</i></b> Expression levels of GRHPR and miR-138-5p were assessed using real-time fluorescent quantitative polymerase chain reaction and Western blot techniques. Bioinformatic analysis was employed to identify miRNAs targeting GRHPR, and the results were confirmed via dual-luciferase reporter assays. HCC cell lines overexpressing GRHPR were established to investigate its roles in cell proliferation, migration, and invasion. The biological function of miR-138-5p targeting GRHPR in HCC cells was also evaluated. Furthermore, a xenograft mouse model was utilized to examine the <i>in vivo</i> functions of GRHPR. <b><i>Results:</i></b> GRHPR expression was downregulated in HCC, whereas miR-138-5p was upregulated. Overexpression of GRHPR suppressed HCC cell proliferation, migration, and invasion. Conversely, inhibition of GRHPR by miR-138-5p promoted HCC cell proliferation and invasive properties. MiR-138-5p was found to regulate Phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) phosphorylation levels by inhibiting GRHPR expression. <b><i>Conclusion:</i></b> This study highlights GRHPR's role as a tumor suppressor in HCC, with its function being regulated by miR-138-5p.</p>","PeriodicalId":55277,"journal":{"name":"Cancer Biotherapy and Radiopharmaceuticals","volume":" ","pages":"733-744"},"PeriodicalIF":2.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Theranostics, Advanced Cancer, and The Meaning of Life.","authors":"J Harvey Turner","doi":"10.1089/cbr.2024.0176","DOIUrl":"10.1089/cbr.2024.0176","url":null,"abstract":"<p><p>There is an unmet need to recognize and address the psychosocial and spiritual support of the rapidly growing population of cancer survivors living with advanced metastatic disease which is essentially incurable. Palliative chemotherapy may do more harm than good. The role of the physician in the provision of a supportive, compassionate relationship of mutual trust is critical in the exploration of spirituality and the meaning of life for each individual patient. The objective must be to enhance quality of life rather than prolong it at any cost. Nuclear physicians are now equipped to offer effective control of advanced metastatic cancer of prostate and neuroendocrine neoplasms without clinically evident toxicity. They also now have the potential to practice phronesis, and in so doing, to significantly ameliorate the quality of life of patients afflicted with these specific advanced cancers. During the time of prolonged symptom-free survival, these patients may be encouraged to find life's meaning and a peaceful acceptance of their inevitable demise.</p>","PeriodicalId":55277,"journal":{"name":"Cancer Biotherapy and Radiopharmaceuticals","volume":" ","pages":"707-711"},"PeriodicalIF":2.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142513375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
William Julian, Olga Sergeeva, Wei Cao, Chunying Wu, Bernadette Erokwu, Chris Flask, Lifang Zhang, Xinning Wang, James Basilion, Sichun Yang, Zhenghong Lee
{"title":"Searching for Protein Off-Targets of Prostate-Specific Membrane Antigen-Targeting Radioligands in the Salivary Glands.","authors":"William Julian, Olga Sergeeva, Wei Cao, Chunying Wu, Bernadette Erokwu, Chris Flask, Lifang Zhang, Xinning Wang, James Basilion, Sichun Yang, Zhenghong Lee","doi":"10.1089/cbr.2024.0066","DOIUrl":"10.1089/cbr.2024.0066","url":null,"abstract":"<p><p><b><i>Background:</i></b> Prostate specific membrane antigen (PSMA)-targeted radioligand therapies represent a highly effective treatment for metastatic prostate cancer. However, high and sustain uptake of PSMA-ligands in the salivary glands led to dose limiting dry mouth (xerostomia), especially with α-emitters. The expression of PSMA and histologic analysis couldn't directly explain the toxicity, suggesting a potential off-target mediator for uptake. In this study, we searched for possible off-target non-PSMA protein(s) in the salivary glands. <b><i>Methods:</i></b> A machine-learning based quantitative structure activity relationship (QSAR) model was built for seeking the possible off-target(s). The resulting target candidates from the model prediction were subjected to further analysis for salivary protein expression and structural homology at key regions required for PSMA-ligand binding. Furthermore, cellular binding assays were performed utilizing multiple cell lines with high expression of the candidate proteins and low expression of PSMA. Finally, PSMA knockout (PSMA-/-) mice were scanned by small animal PET/MR using [<sup>68</sup>Ga]Ga-PSMA-11 for in-vivo validation. <b><i>Results:</i></b> The screening of the trained QSAR model did not yield a solid off-target protein, which was corroborated in part by cellular binding assays. Imaging using PSMA-/- mice further demonstrated markedly reduced PSMA-radioligand uptake in the salivary glands. <b><i>Conclusion:</i></b> Uptake of the PSMA-targeted radioligands in the salivary glands remains primarily PSMA-mediated. Further investigations are needed to illustrate a seemingly different process of uptake and retention in the salivary glands than that in prostate cancer.</p>","PeriodicalId":55277,"journal":{"name":"Cancer Biotherapy and Radiopharmaceuticals","volume":" ","pages":"721-732"},"PeriodicalIF":2.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11824224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142301444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}