Advancing precision therapy for colorectal cancer: Developing clinical indications for multi-target kinase inhibitor
Ya-Chu Tang1, Jing-Jim Ou2, Shu-Ching Hsu3
1Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan.
Abstract:
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.
Insights
A new drug, BPR1J481, shows significant promise in treating colorectal cancer (CRC) by inhibiting SRC kinase and reducing tumor growth. This multi-target kinase inhibitor demonstrated superior efficacy in preclinical models compared to existing treatments.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Colorectal cancer (CRC) incidence and mortality are rising, necessitating novel, effective therapeutics.
- Developing new CRC drugs is hindered by a lack of reliable preclinical models.
Purpose of the Study:
- To evaluate the anti-cancer efficacy and mechanism of the novel multi-target kinase inhibitor BPR1J481 using colorectal cancer patient-derived xenograft (PDX) models.
- To establish clinical indications and demonstrate the advantages of BPR1J481.
Main Methods:
- Utilized colorectal cancer PDX models and derived cell lines for in vivo and in vitro assessments.
- Conducted kinase competitive binding and activity assays to determine BPR1J481's molecular targets.
- Assessed BPR1J481's impact on apoptosis, SRC phosphorylation, angiogenesis (VEGF, PDGF), and compared its efficacy to regorafenib.
Main Results:
- BPR1J481 demonstrated significant anti-cancer efficacy by inducing apoptosis in CRC PDX models.
- BPR1J481 directly inhibited SRC kinase activity, leading to reduced SRC phosphorylation in tumors and cells.
- BPR1J481 suppressed angiogenesis by inhibiting VEGFR2 and PDGFRβ phosphorylation and showed greater efficacy than regorafenib.
Conclusions:
- BPR1J481 exhibits potent anti-cancer effects against colorectal cancer through SRC inhibition and anti-angiogenic mechanisms.
- SRC plays a critical role in CRC progression and prognosis.
- BPR1J481 presents a promising therapeutic candidate for colorectal cancer treatment.
