Advancing precision therapy for colorectal cancer: Developing clinical indications for multi-target kinase inhibitor BPR1J481 using patient-derived xenograft models
The large and rapid increase in the incidence and mortality of colorectal cancer (CRC) demonstrates the urgent need for new drugs with higher efficacy to treat CRC. However, the lack of applicable and reliable preclinical models significantly hinders the progress of drug development. Patient-derived...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-01-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824005012 |
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| author | Ya-Chu Tang Jing-Jim Ou Shu-Ching Hsu Chih-Hsiang Huang Li-Mei Lin Hsin-Huei Chang Yi-Hsin Wang Zih-Ting Huang Manwu Sun Ko-Jiunn Liu Yi-Mei Hung Chi-Yun Lai Chuan Shih Chiung-Tong Chen Jang-Yang Chang Hsing-Pang Hsieh Weir-Torn Jiaang Ching-Chuan Kuo |
| author_facet | Ya-Chu Tang Jing-Jim Ou Shu-Ching Hsu Chih-Hsiang Huang Li-Mei Lin Hsin-Huei Chang Yi-Hsin Wang Zih-Ting Huang Manwu Sun Ko-Jiunn Liu Yi-Mei Hung Chi-Yun Lai Chuan Shih Chiung-Tong Chen Jang-Yang Chang Hsing-Pang Hsieh Weir-Torn Jiaang Ching-Chuan Kuo |
| author_sort | Ya-Chu Tang |
| collection | DOAJ |
| description | The large and rapid increase in the incidence and mortality of colorectal cancer (CRC) demonstrates the urgent need for new drugs with higher efficacy to treat CRC. However, the lack of applicable and reliable preclinical models significantly hinders the progress of drug development. Patient-derived xenograft (PDX) models are currently considered reliable in vivo preclinical models for predicting drug efficacy in cancer patients. This study successfully uses the CRC PDX model to develop clinical indications for the new multi-target kinase inhibitor BPR1J481 and demonstrated the anti-cancer mechanism and competitive advantages of this drug candidate. The results demonstrate that BPR1J481 exhibits significant anticancer efficacy by inducing apoptosis in CRC PDX tumor tissues and corresponding PDX-derived CRC cells. Through kinase competitive binding and kinase activity assays, we discover that BPR1J481 effectively inhibits SRC kinase activity by directly binding to its active site. The reduction in SRC phosphorylation observed in CRC PDX tumor tissues and derived cells upon treatment with BPR1J481 further validates its inhibitory potential. Furthermore, the decrease in viable cells after SRC knockout and the poorer prognosis observed in patients with higher SRC expression, emphasizes the critical significance and clinical relevance of SRC in CRC. Additionally, BPR1J481 exhibits robust anti-angiogenic effects by suppressing VEGF- and PDGF-induced endothelial cell proliferation, migration, and capillary-like tube formation through inhibition of VEGFR2 and PDGFRβ phosphorylation. Remarkably, BPR1J481 appears to demonstrate greater efficacy against CRC compared to regorafenib. These findings highlight the therapeutic potential of BPR1J481 for patients with CRC. |
| format | Article |
| id | doaj-art-c470a68772704ce7a88c9c08fd509768 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-c470a68772704ce7a88c9c08fd5097682025-01-09T06:13:05ZengElsevierPharmacological Research1096-11862025-01-01211107556Advancing precision therapy for colorectal cancer: Developing clinical indications for multi-target kinase inhibitor BPR1J481 using patient-derived xenograft modelsYa-Chu Tang0Jing-Jim Ou1Shu-Ching Hsu2Chih-Hsiang Huang3Li-Mei Lin4Hsin-Huei Chang5Yi-Hsin Wang6Zih-Ting Huang7Manwu Sun8Ko-Jiunn Liu9Yi-Mei Hung10Chi-Yun Lai11Chuan Shih12Chiung-Tong Chen13Jang-Yang Chang14Hsing-Pang Hsieh15Weir-Torn Jiaang16Ching-Chuan Kuo17Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, TaiwanDepartment of Surgery, Chang Bing Show Chwan Memorial Hospital, Changhua County 505029, TaiwanInstitute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County 350401, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, TaiwanNational Institute of Cancer Research, National Health Research Institutes, Tainan City 704016, TaiwanNational Institute of Cancer Research, National Health Research Institutes, Tainan City 704016, TaiwanPathology Core Laboratory, National Health Research Institutes, Miaoli County 350401, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan; Taipei Medical University Hospital, College of Medicine, Taipei Medical University, Taipei City 110301, Taiwan; Taipei Cancer Center, Taiwan; TMU Research Center of Cancer Translational Medicine, 110301, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan; Corresponding authors.Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan; Corresponding authors.The large and rapid increase in the incidence and mortality of colorectal cancer (CRC) demonstrates the urgent need for new drugs with higher efficacy to treat CRC. However, the lack of applicable and reliable preclinical models significantly hinders the progress of drug development. Patient-derived xenograft (PDX) models are currently considered reliable in vivo preclinical models for predicting drug efficacy in cancer patients. This study successfully uses the CRC PDX model to develop clinical indications for the new multi-target kinase inhibitor BPR1J481 and demonstrated the anti-cancer mechanism and competitive advantages of this drug candidate. The results demonstrate that BPR1J481 exhibits significant anticancer efficacy by inducing apoptosis in CRC PDX tumor tissues and corresponding PDX-derived CRC cells. Through kinase competitive binding and kinase activity assays, we discover that BPR1J481 effectively inhibits SRC kinase activity by directly binding to its active site. The reduction in SRC phosphorylation observed in CRC PDX tumor tissues and derived cells upon treatment with BPR1J481 further validates its inhibitory potential. Furthermore, the decrease in viable cells after SRC knockout and the poorer prognosis observed in patients with higher SRC expression, emphasizes the critical significance and clinical relevance of SRC in CRC. Additionally, BPR1J481 exhibits robust anti-angiogenic effects by suppressing VEGF- and PDGF-induced endothelial cell proliferation, migration, and capillary-like tube formation through inhibition of VEGFR2 and PDGFRβ phosphorylation. Remarkably, BPR1J481 appears to demonstrate greater efficacy against CRC compared to regorafenib. These findings highlight the therapeutic potential of BPR1J481 for patients with CRC.http://www.sciencedirect.com/science/article/pii/S1043661824005012Colorectal cancerpatient-derived xenograft modelsmulti-target kinase inhibitorSRC |
| spellingShingle | Ya-Chu Tang Jing-Jim Ou Shu-Ching Hsu Chih-Hsiang Huang Li-Mei Lin Hsin-Huei Chang Yi-Hsin Wang Zih-Ting Huang Manwu Sun Ko-Jiunn Liu Yi-Mei Hung Chi-Yun Lai Chuan Shih Chiung-Tong Chen Jang-Yang Chang Hsing-Pang Hsieh Weir-Torn Jiaang Ching-Chuan Kuo Advancing precision therapy for colorectal cancer: Developing clinical indications for multi-target kinase inhibitor BPR1J481 using patient-derived xenograft models Pharmacological Research Colorectal cancer patient-derived xenograft models multi-target kinase inhibitor SRC |
| title | Advancing precision therapy for colorectal cancer: Developing clinical indications for multi-target kinase inhibitor BPR1J481 using patient-derived xenograft models |
| title_full | Advancing precision therapy for colorectal cancer: Developing clinical indications for multi-target kinase inhibitor BPR1J481 using patient-derived xenograft models |
| title_fullStr | Advancing precision therapy for colorectal cancer: Developing clinical indications for multi-target kinase inhibitor BPR1J481 using patient-derived xenograft models |
| title_full_unstemmed | Advancing precision therapy for colorectal cancer: Developing clinical indications for multi-target kinase inhibitor BPR1J481 using patient-derived xenograft models |
| title_short | Advancing precision therapy for colorectal cancer: Developing clinical indications for multi-target kinase inhibitor BPR1J481 using patient-derived xenograft models |
| title_sort | advancing precision therapy for colorectal cancer developing clinical indications for multi target kinase inhibitor bpr1j481 using patient derived xenograft models |
| topic | Colorectal cancer patient-derived xenograft models multi-target kinase inhibitor SRC |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824005012 |
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