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Controlled extracellular matrix degradation in breast cancer tumors improves therapy by trastuzumab

Ines Beyer1, Zongyi Li, Jonas Persson

  • 1Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|November 18, 2010
PubMed

Insights

Hematopoietic stem cell-delivered relaxin (Rlx) degrades tumor extracellular matrix (ECM), enhancing antibody therapy effectiveness. This approach improved tumor growth control and delayed growth in combination with trastuzumab therapy for breast cancer.

Area of Science:

  • Oncology
  • Biotechnology
  • Molecular Biology

Background:

  • Extracellular matrix (ECM) in solid tumors impedes therapeutic efficacy by blocking drug diffusion and masking target receptors.
  • Her2/neu, a tumor antigen targeted by trastuzumab, is often colocalized with ECM proteins in breast cancer.
  • Current gene delivery methods are inefficient for tumors with extensive ECM.

Purpose of the Study:

  • To investigate if intratumoral expression of relaxin (Rlx) can degrade ECM and enhance trastuzumab therapy.
  • To evaluate a hematopoietic stem cell (HSC)-based approach for Rlx gene delivery to tumors.
  • To assess the impact of Rlx expression on tumor growth and trastuzumab efficacy in breast cancer models.

Main Methods:

  • Immunohistochemical analysis of tumor sections from patients and xenografts.
  • Development of an HSC-based gene delivery system for Rlx.
  • In vivo studies using mouse models with syngeneic and xenograft breast cancer tumors.
  • Combination therapy studies involving Rlx expression and trastuzumab treatment.

Main Results:

  • HSC-mediated Rlx expression led to decreased ECM proteins in mouse breast cancer tumors.
  • Intratumoral Rlx expression resulted in controlled tumor growth.
  • Combining Rlx expression with trastuzumab therapy significantly delayed tumor growth in Her2/neu-positive and treatment-refractory models.

Conclusions:

  • HSC-mediated Rlx gene delivery is a viable strategy for ECM degradation in solid tumors.
  • Relaxin expression enhances the effectiveness of antibody-based cancer therapies like trastuzumab.
  • This approach holds promise for improving various anticancer treatments, including T-cell therapies and chemotherapy.

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