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VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma
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Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse

Nicolas Boisgerault1, Timothy Kottke, Jose Pulido

  • 1Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|June 12, 2013
PubMed

Insights

Recurrent tumors overexpress topoisomerase-IIα (TOPO-IIα), a target for novel therapies. This discovery enables new treatments for aggressive cancer regrowth after initial therapy, improving patient outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Recurrent tumors pose a significant clinical challenge due to aggressive regrowth after treatment-induced dormancy.
  • Identifying specific antigens on recurrent tumors is crucial for developing effective second-line therapies.

Purpose of the Study:

  • To identify recurrence-specific tumor antigens using a vesicular stomatitis virus (VSV)-expressed cDNA library.
  • To investigate the role of topoisomerase-IIα (TOPO-IIα) as a target antigen in recurrent prostate and melanoma tumors.
  • To evaluate combination therapies for treating recurrent tumors resistant to frontline treatments.

Main Methods:

  • Screening of a VSV-cDNA library derived from recurrent tumor cells.
  • Comparative analysis of TOPO-IIα expression in primary versus recurrent tumors (prostate and melanoma).
  • In vivo studies utilizing combination therapies (including doxorubicin) in mouse models.

Main Results:

  • Topoisomerase-IIα (TOPO-IIα) was identified as a recurrence-specific tumor antigen.
  • Recurrent tumors (prostate and melanoma) showed significantly higher TOPO-IIα expression compared to primary tumors.
  • Recurrent tumors exhibited a novel sensitivity to doxorubicin (DOX) chemotherapy.
  • Combination therapies successfully cured mice with recurrent tumors that would otherwise relapse.

Conclusions:

  • Recurrent tumors express distinct antigens compared to primary tumors, identifiable via VSV-cDNA library technology.
  • TOPO-IIα is a promising target for breaking tolerance in recurrent cancers.
  • The findings suggest the potential for developing common second-line therapies against various tumor recurrences, potentially using agents with limited primary tumor activity.

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