Tumor-specific gene therapy for pancreatic cancer using human neural stem cells encoding carboxylesterase
Sung S Choi1, Kichul Yoon1,2,3, Seon-A Choi4
1Biomedical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea.
Abstract:
Advanced pancreatic cancer is one of the most lethal malignant human diseases lacking effective treatment. Its extremely low survival rate necessitates development of novel therapeutic approach. Human neural stem cells (NSCs) are known to have tumor-tropic effect. We genetically engineered them to express rabbit carboxyl esterase (F3.CE), which activates prodrug CPT-11(irinotecan) into potent metabolite SN-38. We found significant inhibition of the growth of BxPC3 human pancreatic cancer cell line in vitro by F3.CE in presence of CPT-11. Apoptosis was also markedly increased in BxPC3 cells treated with F3.CE and CPT-11. The ligand VEGF and receptor VEGF-1(Flt1) were identified to be the relevant tumor-tropic chemoattractant. We confirmed in vivo that in mice injected with BxPC3 on their skin, there was significant reduction of tumor size in those treated with both F3.CE and BxPC3 adjacent to the cancer mass. Administration of F3.CE in conjunction with CPT-11 could be a new possibility as an effective treatment regimen for patients suffering from advanced pancreatic cancer.
Insights
Genetically engineered neural stem cells (NSCs) expressing rabbit carboxyl esterase (F3.CE) effectively activated CPT-11 into SN-38, significantly inhibiting pancreatic cancer growth and increasing apoptosis in preclinical models.
Area of Science:
- Oncology
- Cancer Therapy
- Stem Cell Biology
Background:
- Advanced pancreatic cancer has a poor prognosis and limited treatment options.
- Novel therapeutic strategies are urgently needed to improve patient survival rates.
- Human neural stem cells (NSCs) possess inherent tumor-tropic properties.
Purpose of the Study:
- To develop a targeted cancer therapy using genetically engineered NSCs.
- To evaluate the efficacy of F3.CE-expressing NSCs in activating CPT-11 for pancreatic cancer treatment.
- To investigate the tumor-tropic mechanisms of engineered NSCs.
Main Methods:
- Genetic engineering of human neural stem cells (NSCs) to express rabbit carboxyl esterase (F3.CE).
- In vitro studies using BxPC3 human pancreatic cancer cells treated with F3.CE and CPT-11.
- In vivo studies in mice bearing BxPC3 tumors treated with F3.CE.
- Identification of VEGF and VEGF-1 (Flt1) as chemoattractants mediating tumor tropism.
Main Results:
- F3.CE in combination with CPT-11 significantly inhibited BxPC3 pancreatic cancer cell growth in vitro.
- Treatment with F3.CE and CPT-11 markedly increased apoptosis in BxPC3 cells.
- In vivo studies demonstrated significant tumor size reduction in mice treated with F3.CE adjacent to cancer masses.
- VEGF/VEGF-1 signaling was confirmed as a key factor in NSC tumor-homing.
Conclusions:
- Engineered neural stem cells expressing F3.CE offer a promising approach for targeted pancreatic cancer therapy.
- The combination of F3.CE-expressing NSCs and CPT-11 represents a potential novel treatment regimen for advanced pancreatic cancer.
- Targeting tumor-tropic mechanisms and prodrug activation provides a viable strategy for enhancing anti-cancer efficacy.
