TY - JOUR
T1 - Porphyrin modified trastuzumab improves efficacy of HER2 targeted photodynamic therapy of gastric cancer
AU - Korsak, Barbara
AU - Almeida, Gabriela M.
AU - Rocha, Sara
AU - Pereira, Carla
AU - Mendes, Nuno
AU - Osório, Hugo
AU - Pereira, Patrícia M.R.
AU - Rodrigues, João M.M.
AU - Schneider, Rudolf J.
AU - Sarmento, Bruno
AU - Tomé, João P.C.
AU - Oliveira, Carla
N1 - Publisher Copyright:
© 2017 UICC
PY - 2017/10/1
Y1 - 2017/10/1
N2 - Gastric cancer (GC) is the 3rd deadliest cancer worldwide, due to limited treatment options and late diagnosis. Human epidermal growth factor receptor-2 (HER2) is overexpressed in ∼20% of GC cases and anti-HER2 antibody trastuzumab in combination with conventional chemotherapy, is recognized as standard therapy for HER2-positive metastatic GC. This strategy improves GC patients' survival by 2–3 months, however its optimal results in breast cancer indicate that GC survival may be improved. A new photoimmunoconjugate was developed by conjugating a porphyrin with trastuzumab (Trast:Porph) for targeted photodynamic therapy in HER2-positive GC. Using mass spectrometry analysis, the lysine residues in the trastuzumab structure most prone for porphyrin conjugation were mapped. The in vitro data demonstrates that Trast:Porph specifically binds to HER2-positive cells, accumulates intracellularly, co-localizes with lysosomal marker LAMP1, and induces massive HER2-positive cell death upon cellular irradiation. The high selectivity and cytotoxicity of Trast:Porph based photoimmunotherapy is confirmed in vivo in comparison with trastuzumab alone, using nude mice xenografted with a HER2-positive GC cell line. In the setting of human disease, these data suggest that repetitive cycles of Trast:Porph photoimmunotherapy may be used as an improved treatment strategy in HER2-positive GC patients.
AB - Gastric cancer (GC) is the 3rd deadliest cancer worldwide, due to limited treatment options and late diagnosis. Human epidermal growth factor receptor-2 (HER2) is overexpressed in ∼20% of GC cases and anti-HER2 antibody trastuzumab in combination with conventional chemotherapy, is recognized as standard therapy for HER2-positive metastatic GC. This strategy improves GC patients' survival by 2–3 months, however its optimal results in breast cancer indicate that GC survival may be improved. A new photoimmunoconjugate was developed by conjugating a porphyrin with trastuzumab (Trast:Porph) for targeted photodynamic therapy in HER2-positive GC. Using mass spectrometry analysis, the lysine residues in the trastuzumab structure most prone for porphyrin conjugation were mapped. The in vitro data demonstrates that Trast:Porph specifically binds to HER2-positive cells, accumulates intracellularly, co-localizes with lysosomal marker LAMP1, and induces massive HER2-positive cell death upon cellular irradiation. The high selectivity and cytotoxicity of Trast:Porph based photoimmunotherapy is confirmed in vivo in comparison with trastuzumab alone, using nude mice xenografted with a HER2-positive GC cell line. In the setting of human disease, these data suggest that repetitive cycles of Trast:Porph photoimmunotherapy may be used as an improved treatment strategy in HER2-positive GC patients.
KW - HER2
KW - gastric cancer
KW - photoimmunoconjugate
KW - photoimmunotherapy
KW - trastuzumab
UR - http://www.scopus.com/inward/record.url?scp=85022335625&partnerID=8YFLogxK
U2 - 10.1002/ijc.30844
DO - 10.1002/ijc.30844
M3 - Article
C2 - 28639285
AN - SCOPUS:85022335625
SN - 0020-7136
VL - 141
SP - 1478
EP - 1489
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 7
ER -