Treatment of Triple-Negative Breast Cancer Using Anti-EGFR–Directed Radioimmunotherapy Combined with Radiosensitizing Chemotherapy and PARP Inhibitor

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 177 Lulabeled 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.

Targeted Chemoradiation in Metastatic Colorectal Cancer: A Phase I Trial of 131I-huA33 with Concurrent Capecitabine

“…The combination of radioimmunotherapy with chemotherapy to induce enhanced antitumor effects has been extensively explored in preclinical models (23)(24)(25)(26)(27)(28) and in a small number of phase I/II studies in patients with advanced solid tumors, with a suggestion of antitumor activity in some (29)(30)(31)(32)(33)(34). The aim of this approach is to use chemotherapy as a radiosensitizer, so that cancer cell cycle is arrested in the radiosensitive G(2)/M phase and efficacy is improved.…”

Gemcitabine and CHK1 Inhibition Potentiate EGFR-Directed Radioimmunotherapy against Pancreatic Ductal Adenocarcinoma

“…PANC-1 and BxPC-3 cells expressing luciferase were prepared by transduction with the luciferase expressing retrovirus as described previously (16). The hybridoma producing the anti-human EGFR mouse mAb (clone 225 HB-8508; IgG1; ATCC) was cultured as per ATCC instructions.…”

“…The EGFR mAb was purified, conjugated to DOTA-NHS-ESTER (Macrocyclics), radiolabeled with 177 LuCl 3 (Perkin Elmer), and confirmed for immunoreactivity and stability as described elsewhere (16). The specific activity of 177 Luanti-EGFR mAb ranged between 2 and 3 mCi/mg (74-111 MBq/mg).…”

Characterization of PI (breast cancer cell special peptide) in MDA-MB-231 breast cancer cells and its potential therapeutic applications

“…MDA-MB-231 and MDA-MB-435 (1x10 5 ) cells were incubated with 200 ng/ml of PI-GST in culture medium for 8-12 h at 37˚C, and washed six times with PBS. Then, the cultured cells were fixed in 10% Triton X-100 for 10 min, and detected by 30-min incubation with FITCconjugated mouse monoclonal antibody (anti-GST-FITC) (Santa Cruz).…”

“…It represents up to 20% of all breast cancers and currently has no standard treatment (4). In the past five years, evidence has emerged indicating that TNBC is associated with the inactivation of BRCA1 and overexpression of epidermal growth factor receptor (EGFR), which makes it sensitive to anti-EGFR therapies (5). Additionally, novel molecular-targeted treatments focusing on tyrosine kinase inhibitors (TKI) (6), anti-angiogenesis [vascular endothelial growth factor (VEGF) antibody] (7), and the key enzymes of cellular DNA repair such as poly-ADP ribose polymerase 1 (PARP1) (8,9), have been developed but are still undergoing trials.…”