Combined Treatment with Epigenetic, Differentiating, and Chemotherapeutic Agents Cooperatively Targets

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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

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Vanessa F Merino1, Nguyen Nguyen1, Kideok Jin1

  • 1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Cancer Research
|January 21, 2016
PubMed

Insights

Combining entinostat, all-trans retinoic acid (ATRA), and doxorubicin (EAD) effectively treats triple-negative breast cancer (TNBC) by inducing cancer cell differentiation and restoring silenced gene expression, leading to significant tumor regression.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Stem Cell Biology

Background:

  • All-trans retinoic acid (ATRA) shows limited success in cancer stem cell differentiation due to epigenetic silencing of the retinoic acid receptor (RAR)-β.
  • Entinostat, a histone deacetylase inhibitor, is a promising antitumor agent for breast cancer.
  • The combined effects of epigenetic, differentiation, and chemotherapy against triple-negative breast cancer (TNBC) remain largely unexplored.

Purpose of the Study:

  • To investigate the efficacy of a combined epigenetic, differentiation, and chemotherapeutic approach using entinostat, ATRA, and doxorubicin (EAD) against TNBC.
  • To evaluate the impact of EAD treatment on tumor regression, RAR-β expression, and cancer stem cell differentiation in TNBC models.

Main Methods:

  • Treatment of TNBC xenografts and patient-derived metastatic cells with entinostat, ATRA, and doxorubicin (EAD).
  • Assessment of tumor regression, RAR-β expression, and topoisomerase II-β (TopoII-β) activity.
  • Analysis of breast tumor-initiating cell differentiation and gene expression, including the role of ETS transcription factor-1 (ESE-1/ELF3).

Main Results:

  • Combined EAD treatment led to significant tumor regression in TNBC xenografts.
  • EAD therapy restored epigenetically silenced RAR-β expression by inhibiting TopoII-β-mediated transcriptional silencing.
  • EAD was highly effective in inducing differentiation of breast tumor-initiating cells in vivo, with ESE-1/ELF3 enhancing this effect.
  • Patient-derived metastatic cells also responded positively to EAD treatment.

Conclusions:

  • Entinostat, doxorubicin, and ATRA (EAD) combination therapy demonstrates significant efficacy in treating TNBC.
  • The EAD regimen potentiates doxorubicin-induced cytotoxicity and ATRA-driven differentiation, leading to substantial tumor regression.
  • This triple therapy approach offers a promising strategy for managing TNBC by targeting epigenetic silencing and promoting cellular differentiation.

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