Pharmacologically enhanced expression of GPNMB increases the sensitivity of melanoma cells to the CR011-vcMMAE antibody-drug conjugate.
GPNMB is a melanoma-associated glycoprotein that is targeted by the CR011-vcMMAE antibody-drug conjugate (ADC). Previous studies have shown that CR011-vcMMAE induces the apoptosis of GPNMB-expressing tumor cells in vitro and tumor regression in xenograft models. This ADC is currently in clinical trials for melanoma. In the present investigation, a variety of compounds were examined for their ability to increase the expression of GPNMB by cancer cells. These experiments lead to the identification of three distinct groups of compounds that increased GPNMB, some of which were shown to enhance the sensitivity of melanoma cells to CR011-vcMMAE. These data indicate that it may be possible to increase the anticancer activity of CR011-vcMMAE through pharmacological enhancement of GPNMB expression for potential therapeutic benefit.
Qian
Xiaozhong
X
CuraGen Corporation, Branford, CT 06405, USA.
Mills
Evan
E
Torgov
Michael
M
LaRochelle
William J
WJ
Jeffers
Michael
M
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology* / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics*
D000911:Antibodies, Monoclonal; C541991:CR011-vcMMAE; D004791:Enzyme Inhibitors; C503042:GPNMB protein, human; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D048049:Extracellular Signal-Regulated MAP Kinases