Purpose: Considerable preclinical and clinical data indicate that only a small subset of tumor cells has longterm proliferating capacity. These cells are termed cancer stem cells (CSCs). Failure to eradicate CSCs is
hypothesized to be a cause of cancer recurrence after potentially curative therapies. Therefore, approaches
that target CSCs have the potential to improve outcomes. We evaluated the combination of vorinostat and
lapatinib to target CSCs and metastasis.
Experimental Design: We conducted preclinical studies and a phase I/II clinical trial to determine the
effects of vorinostat and lapatinib to CSCs.
Results: Our preclinical studies demonstrated that vorinostat and lapatinib further reduced CSCs compared
to either single agent. Reduction in self-renewal proteins, mammospheres, epithelial-mesenchymal
transition (EMT) markers, and cell migration was also observed. Based on these findings, the combination
was evaluated in the phase I trial to which a total of 12 patients were enrolled. Dose-limiting toxicity was
not observed in phase I, and the recommended phase II dose was vorinostat 400 mg 4 days on 3 days off
and lapatinib 1,250 mg daily. In HER2-positive breast cancer patients, the clinical benefit rate was observed
in 43% of subjects. Interestingly, patients who remained on vorinostat and lapatinib did not develop any
new site of metastasis.
Conclusion: The combination of vorinostat and lapatinib is safe and active in HER2-positive breast cancer.
Further studies are needed to evaluate this strategy to target CSCs and metastasis.
Polymer–lipid hybrid anti-HER2 nanoparticles for targeted salinomycin delivery to HER2-positive breast cancer stem cells and cancer cells
