TY - JOUR
T1 - Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse
AU - Boisgerault, Nicolas
AU - Kottke, Timothy
AU - Pulido, Jose
AU - Thompson, Jill
AU - Diaz, Rosa Maria
AU - Rommelfanger-Konkol, Diana
AU - Embry, Addie
AU - Saenz, Dyana
AU - Poeschla, Eric
AU - Pandha, Hardev
AU - Harrington, Kevin
AU - Melcher, Alan
AU - Selby, Peter
AU - Vile, Richard
N1 - Funding Information:
We thank Toni Higgins and Nicole Goldman for expert secretarial assistance. This work is supported by the Richard M Schulze Family Foundation, the Mayo Foundation, Cancer Research UK, the National Institute of Health (R01CA107082, R01CA130878, and R01CA132734), and a grant from Terry and Judith Paul. The authors declare no conflict of interest.
PY - 2013/8
Y1 - 2013/8
N2 - Aggressive regrowth of recurrent tumors following treatment-induced dormancy represents a major clinical challenge for treatment of malignant disease. We reported previously that recurrent prostate tumors, which underwent complete macroscopic regression followed by aggressive regrowth, could be cured with a vesicular stomatitis virus (VSV)-expressed cDNA library derived from recurrent tumor cells. By screening the protective, recurrence-derived VSV-cDNA library, here we identify topoisomerase-IIα (TOPO-IIα) as a recurrence-specific tumor antigen against which tolerance can be broken. Tumor recurrences, in two different types of tumor (prostate and melanoma), which had evaded two different frontline treatments (immunotherapy or chemotherapy), significantly overexpressed TOPO-IIα compared with their primary tumor counterparts, which conferred a novel sensitivity to doxorubicin (DOX) chemotherapy upon the recurrent tumors. This was exploited in vivo using combination therapies to cure mice, which would otherwise have relapsed, after suboptimal primary therapy in both models. Our data show that recurrent tumors - across histologies and primary treatments - express distinct antigens compared with the primary tumor which can be identified using the VSV-cDNA library technology. These results suggest that it may be possible to design a few common second-line therapies against a variety of tumor recurrences, in some cases using agents with no obvious activity against the primary tumor.
AB - Aggressive regrowth of recurrent tumors following treatment-induced dormancy represents a major clinical challenge for treatment of malignant disease. We reported previously that recurrent prostate tumors, which underwent complete macroscopic regression followed by aggressive regrowth, could be cured with a vesicular stomatitis virus (VSV)-expressed cDNA library derived from recurrent tumor cells. By screening the protective, recurrence-derived VSV-cDNA library, here we identify topoisomerase-IIα (TOPO-IIα) as a recurrence-specific tumor antigen against which tolerance can be broken. Tumor recurrences, in two different types of tumor (prostate and melanoma), which had evaded two different frontline treatments (immunotherapy or chemotherapy), significantly overexpressed TOPO-IIα compared with their primary tumor counterparts, which conferred a novel sensitivity to doxorubicin (DOX) chemotherapy upon the recurrent tumors. This was exploited in vivo using combination therapies to cure mice, which would otherwise have relapsed, after suboptimal primary therapy in both models. Our data show that recurrent tumors - across histologies and primary treatments - express distinct antigens compared with the primary tumor which can be identified using the VSV-cDNA library technology. These results suggest that it may be possible to design a few common second-line therapies against a variety of tumor recurrences, in some cases using agents with no obvious activity against the primary tumor.
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U2 - 10.1038/mt.2013.116
DO - 10.1038/mt.2013.116
M3 - Article
C2 - 23752316
AN - SCOPUS:84881310761
SN - 1525-0016
VL - 21
SP - 1507
EP - 1516
JO - Molecular Therapy
JF - Molecular Therapy
IS - 8
ER -