The polo-like kinase 4 (PLK-4) has recently emerged as a target that strongly correlates with aggressive tumor growth, high levels of hypoxia and metastasis in patient-derived pancreatic xenografts. In contrast to other members of the PLK family, the role of PLK-4 in cancer remains mostly elusive. Overexpression of PLK-4 in tumors has been suggested to contribute to chromosomal instability due to its crucial role in centriole duplication and therefore presents an interesting molecular target for the development of new therapeutic options for pancreatic cancer patients. The newly developed PLK-4 inhibitor CFI-400945 has been shown to specifically target PLK-4, resulting in incorrect centriole duplication and is currently developed for clinical trials.
We used 6 orthotopically implanted patient-derived pancreatic xenograft models with varying growth rates and levels of tumor hypoxia in order to investigate the efficiency of the PLK-4 inhibitor CFI-400945 as a mono-therapy or in combination with Gemcitabine. Animals were treated with CFI-400945 using a daily dose of 7.5mg/kg for 21 days for experiments evaluating activity as a mono-therapy or with 13.5mg/kg according to a 2-day-on-5-days-off schedule in combination bi-weekly 100mg/kg Gemcitabine for 21 days. Tumor weight after completion of the treatment and overall survival were evaluated. Immunofluorescence (IF) staining of xenograft sections was used to evaluate PLK-4 inhibition, tumor hypoxia and proliferation.
Treatment with CFI-400945 as a mono-therapy for 21 days significantly reduced tumor weight in 4 of the 6 tested patient-derived pancreatic xenograft models and an increase in overall survival in a number of responsive models. The strongest response to CFI-400945 treatment was observed in the highly hypoxic fast growing xenograft models OCIP51 where medium survival was 103days in the treatment group when compared to 54 days in vehicle treated animals. Experiments investigating the benefit of the combination of CFI-400945 with Gemcitabine using a clinically relevant treatment schedule are currently in progress in 2 xenograft models and will be completed shortly.
We furthermore examined the correlation between tumor hypoxia, proliferation and response to CFI-400945 treatment in order to establish biological correlates for treatment response. Preliminary results show that although tumor weight was reduced in most of the tested models, the strongest response to CFI-400945 as a mono-therapy was observed in highly hypoxic models when compared to medium or low hypoxic models.
These findings suggest that the PLK-4 inhibitor CFI-400945 may provide an effective treatment strategy for pancreatic cancer patients.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B282.
Citation Format: Ines Lohse, Pinjiang Cao, Trevor Do, Emin Ibrahimov, Ming-Sound Tsao, David W. Hedley. The PLK-4 inhibitor CFI-400945 reduces tumor growth in patient-derived pancreatic xenografts. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B282.