Treatment of triple-negative breast cancer using anti-EGFR-directed radioimmunotherapy combined with radiosensitizing chemotherapy and PARP inhibitor

Al-Ejeh, Fares, Shi, Wei, Miranda, Mariska, Simpson, Peter T., Vargas, Ana Cristina, Song, Sarah, Wiegmans, Adrian P., Swarbrick, Alex, Welm, Alana L., Brown, Michael P., Chenevix-Trench, Georgia, Lakhani, Sunil R. and Khanna, Kum Kum (2013) Treatment of triple-negative breast cancer using anti-EGFR-directed radioimmunotherapy combined with radiosensitizing chemotherapy and PARP inhibitor. Journal of Nuclear Medicine, 54 6: 913-921. doi:10.2967/jnumed.112.111534


Author Al-Ejeh, Fares
Shi, Wei
Miranda, Mariska
Simpson, Peter T.
Vargas, Ana Cristina
Song, Sarah
Wiegmans, Adrian P.
Swarbrick, Alex
Welm, Alana L.
Brown, Michael P.
Chenevix-Trench, Georgia
Lakhani, Sunil R.
Khanna, Kum Kum
Title Treatment of triple-negative breast cancer using anti-EGFR-directed radioimmunotherapy combined with radiosensitizing chemotherapy and PARP inhibitor
Journal name Journal of Nuclear Medicine   Check publisher's open access policy
ISSN 0161-5505
1535-5667
Publication date 2013-06-01
Sub-type Article (original research)
DOI 10.2967/jnumed.112.111534
Volume 54
Issue 6
Start page 913
End page 921
Total pages 9
Place of publication Reston, VA, United States
Publisher Society of Nuclear Medicine
Collection year 2014
Language eng
Abstract Triple-negative breast cancer (TNBC) is associated with poor survival. Chemotherapy is the only standard treatment for TNBC. The prevalence of BRCA1 inactivation in TNBC has rationalized clinical trials of poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. Similarly, the overexpression of epidermal growth factor receptor (EGFR) rationalized anti-EGFR therapies in this disease. However, clinical trials using these 2 strategies have not reached their promise. In this study, we used EGFR as a target for radioimmunotherapy and hypothesized that EGFR-directed radioimmunotherapy can deliver a continuous lethal radiation dose to residual tumors that are radiosensitized by PARP inhibitors and chemotherapy. Methods: We analyzed EGFR messenger RNA in published gene expression array studies and investigated EGFR protein expression by immunohistochemistry in a cohort of breast cancer patients to confirm EGFR as a target in TNBC. Preclinically, using orthotopic and metastatic xenograft models of EGFR-positive TNBC, we investigated the effect of the novel combination of 177Lulabeled anti-EGFR monoclonal antibody, chemotherapy, and PARP inhibitors on cell death and the survival of breast cancer stem cells. Results: In this first preclinical study of anti-EGFR radioimmunotherapy in breast cancer, we found that anti-EGFR radioimmunotherapy is safe and that TNBC orthotopic tumors and established metastases were eradicated in mice treated with anti-EGFR radioimmunotherapy combined with chemotherapy and PARP inhibitors. We showed that the superior response to this triple-agent combination therapy was associated with apoptosis and eradication of putative breast cancer stem cells. Conclusion: Our data support further preclinical investigations toward the development of combination therapies using systemic anti-EGFR radioimmunotherapy for the treatment of recurrent and metastatic TNBC.
Keyword Combination therapy
EGFR
PARP inhibitor
Radioimmunotherapy
Triple-negative breast cancer
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Tue, 14 May 2013, 21:31:17 EST by Dr Sarah Song on behalf of Institute for Molecular Bioscience