Verteporfin-loaded microparticles for radiosensitization of preclinical lung and breast metastatic spine cancer.

Abstract

OBJECTIVE:

The vertebral column is the most common site for skeletal metastasis, often leading to debilitating pain and weakness. Metastatic cancer has unique genetic drivers that potentiate tumorigenicity. There is an unmet need for novel targeted therapy in patients with spinal metastatic disease.

METHODS:

The authors assessed the effect of verteporfin-induced yes-associated protein (YAP) inhibition on spine metastatic cell tumorigenicity and radiation sensitivity in vitro. Animal studies used a subcutaneous xenograft mouse model to assess the use of systemic intraperitoneal verteporfin (IP-VP) and intratumoral verteporfin microparticles (IT-VP) to inhibit the tumorigenicity of lung and breast spinal metastatic tumors from primary patient-derived tissue.

RESULTS:

Verteporfin led to a dose-dependent decrease in migration, clonogenicity, and cell viability via inhibition of YAP and downstream effectors cyclin D1, CTGF, TOP2A, ANDRD1, MCL-1, FOSL2, KIF14, and KIF23. This was confirmed with knockdown of YAP. Verteporfin has an additive response when combined with radiation, and knockdown of YAP rendered cells more sensitive to radiation. The addition of verteporfin to YAP knockdown cells did not significantly alter migration, clonogenicity, or cell viability. IP-VP and IT-VP led to diminished tumor growth (p < 0.0001), especially when combined with radiation (p < 0.0001). Tissue analysis revealed diminished expression of YAP (p < 0.0001), MCL-1 (p < 0.0001), and Ki-67 (p < 0.0001) in tissue from verteporfin-treated tumors compared with vehicle-treated tumors.

CONCLUSIONS:

This is the first study to demonstrate that verteporfin-mediated inhibition of YAP leads to diminished tumorigenicity in lung and breast spinal metastatic cancer cells. Targeting of YAP with verteporfin offers promising results that could be translated to human clinical trials.

• Authors: Oluwaseun O Akinduro, Paola Suarez-Meade, McKinley Roberts, Stephany Y Tzeng, Rachel Sarabia-Estrada, Paula Schiapparelli, Emily S Norton, Ziya L Gokaslan, Panos Z Anastasiadis, Hugo Guerrero-Cázares, Jordan J Green, Alfredo Quiñones-Hinojosa
• Journal: Journal of neurosurgery. Spine (J Neurosurg Spine) Vol. 38 Issue 4 Pg. 481-493 (04 01 2023) ISSN: 1547-5646 [Electronic] United States
• PMID: 36585863 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Verteporfin
• Myeloid Cell Leukemia Sequence 1 Protein
• Transcription Factors

Topics

• Humans
• Animals
• Mice
• Female
• Verteporfin (pharmacology, therapeutic use)
• Myeloid Cell Leukemia Sequence 1 Protein
• Transcription Factors (metabolism, pharmacology)
• Cell Line, Tumor
• Breast Neoplasms (drug therapy)
• Lung (metabolism)
• Cell Proliferation