Targeting mutant p53 protein and the tumor vasculature

An effective combination therapy for advanced breast tumors

Yayun Liang, Cynthia Besch-Williford, Indira Benakanakere, Philip E. Thorpe, Salman M. Hyder

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Breast cancer progression depends upon the elaboration of a vasculature sufficient for the nourishment of the developing tumor. Breast tumor cells frequently contain a mutant form of p53 (mtp53), a protein which promotes their survival. The aim of this study was to determine whether combination therapy targeting mtp53 and anionic phospholipids (AP) on tumor blood vessels might be an effective therapeutic strategy for suppressing advanced breast cancer. We examined the therapeutic effects, singly, or in combination, of p53 reactivation and induction of massive apoptosis (PRIMA-1), which reactivates mtp53 and induces tumor cell apoptosis, and 2aG4, a monoclonal antibody that disrupts tumor vasculature by targeting AP on the surface of tumor endothelial cells and causes antibody-dependent destruction of tumor blood vessels, leading to ischemia and tumor cell death. Xenografts from two tumor cell lines containing mtp53, BT-474 and HCC-1428, were grown in nude mice to provide models of advanced breast tumors. After treatment with PRIMA-1 and/or 2aG4, regressing tumors were analyzed for vascular endothelial growth factor (VEGF) expression, blood vessel loss, and apoptotic markers. Individual drug treatment led to partial suppression of breast cancer progression. In contrast, combined treatment with PRIMA-1 and 2aG4 was extremely effective in suppressing tumor growth in both models and completely eradicated approximately 30% of tumors in the BT-474 model. Importantly, no toxic effects were observed in any treatment group. Mechanistic studies determined that PRIMA-1 reactivated mtp53 and also exposed AP on the surface of tumor cells as determined by enhanced 2aG4 binding. Combination treatment led to significant induction of tumor cell apoptosis, loss of VEGF expression, as well as destruction of tumor blood vessels. Furthermore, combination treatment severely disrupted tumor blood vessel perfusion in both tumor models. The observed in vitro PRIMA-1-induced exposure of tumor epithelial cell AP might provide a target for 2aG4 and contribute to the increased effectiveness of such combination therapy in vivo. We conclude that the combined targeting of mtp53 and the tumor vasculature is a novel effective strategy for combating advanced breast tumors.

Original languageEnglish (US)
Pages (from-to)407-420
Number of pages14
JournalBreast Cancer Research and Treatment
Volume125
Issue number2
DOIs
StatePublished - Jan 2011

Fingerprint

Mutant Proteins
Breast Neoplasms
Vascular Tissue Neoplasms
Neoplasms
Therapeutics
Phospholipids
Apoptosis
Vascular Endothelial Growth Factor A
Poisons
Therapeutic Uses
Tumor Cell Line
Heterografts
Nude Mice
Blood Vessels
Cell Death
Ischemia
Endothelial Cells
Perfusion
Epithelial Cells
Monoclonal Antibodies

Keywords

  • Apoptosis
  • Blood vessel targeting agent
  • Breast tumor growth
  • Cell proliferation
  • p53
  • p53 Reactivation and induction of massive apoptosis (PRIMA-1)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeting mutant p53 protein and the tumor vasculature : An effective combination therapy for advanced breast tumors. / Liang, Yayun; Besch-Williford, Cynthia; Benakanakere, Indira; Thorpe, Philip E.; Hyder, Salman M.

In: Breast Cancer Research and Treatment, Vol. 125, No. 2, 01.2011, p. 407-420.

Research output: Contribution to journalArticle

Liang, Yayun ; Besch-Williford, Cynthia ; Benakanakere, Indira ; Thorpe, Philip E. ; Hyder, Salman M. / Targeting mutant p53 protein and the tumor vasculature : An effective combination therapy for advanced breast tumors. In: Breast Cancer Research and Treatment. 2011 ; Vol. 125, No. 2. pp. 407-420.
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