Liver cancer protease activity profiles support therapeutic options with matrix metalloproteinase-activatable oncolytic measles virus.
Primary and secondary cancers of the liver are a significant health problem with limited treatment options. We sought here to develop an oncolytic measles virus (MV) preferentially activated in liver tumor tissue, thus reducing infection and destruction of healthy tissue. We documented that in primary tumor tissue, urokinase-type plasminogen activator and especially matrix metalloproteinase-2 (MMP-2) are significantly more active than in adjacent nontumorous tissue. We then generated variants of the MV fusion protein by inserting different MMP substrate motifs at the protease cleavage site and identified the motif PQGLYA as the most efficient cleavage site as determined by syncytia formation on protease-positive tumor cells. The corresponding MMP-activatable oncolytic MV-MMPA1 virus was rescued and shown to be strongly restricted on primary human hepatocytes and healthy human liver tissue, while remaining as effective as the parental MV in the tumor tissue sections. Our findings underline the clinical potency of the MMP activation concept as a strategy to generate safer oncolytic viruses for the treatment of primary and secondary cancers of the liver.
Mühlebach
Michael D
MD
Division of Medical Biotechnology and Biostatistics Section, Paul-Ehrlich-Institut, Langen, Germany.
Schaser
Thomas
T
Zimmermann
Martina
M
Armeanu
Sorin
S
Hanschmann
Kay-Martin O
KM
Cattaneo
Roberto
R
Bitzer
Michael
M
Lauer
Ulrich M
UM
Cichutek
Klaus
K
Buchholz
Christian J
CJ
D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000556:secondary / Q000628:therapy / Q000821:virology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008459:Measles virus / Q000502:physiology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D010447:Peptide Hydrolases / Q000378:metabolism*; D014162:Transfection; D014709:Vero Cells; D014760:Viral Fusion Proteins / Q000378:metabolism
D014760:Viral Fusion Proteins; D010447:Peptide Hydrolases; D020782:Matrix Metalloproteinases