Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse

Nicolas Boisgerault, Timothy Kottke, Jose Pulido, Jill Thompson, Rosa Maria Diaz, Diana Rommelfanger-Konkol, Addie Embry, Dyana Saenz, Eric Poeschla, Hardev Pandha, Kevin Harrington, Alan Melcher, Peter Selby, Richard Vile

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27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1507-1516
Number of pages10
JournalMolecular Therapy
Volume21
Issue number8
DOIs
StatePublished - Aug 2013

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Boisgerault, N., Kottke, T., Pulido, J., Thompson, J., Diaz, R. M., Rommelfanger-Konkol, D., Embry, A., Saenz, D., Poeschla, E., Pandha, H., Harrington, K., Melcher, A., Selby, P., & Vile, R. (2013). Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse. Molecular Therapy, 21(8), 1507-1516. https://doi.org/10.1038/mt.2013.116