P4-03-03: Therapeutic Sensitivities of Mouse Models of Human Breast Cancer.
Authors: Usary JE , Darr DB , Zhao W , Balletta LD , Aparicio AP , Karginova OA , Jordan JL , Perou CM 
Published: June 2012

Genetically engineered mouse (GEM) models have provided a wealth of information regarding the genetic causes of cancer, but their utility for preclinical drug evaluation has not been well examined. Here we have used three mammary tumor GEM models that represent three human breast cancer subtypes and have evaluated their sensitivities to chemotherapy and to three biologically targeted agents. We have selected three mouse models that resemble human breast cancer subtypes based upon common gene expression profiles; Basal-like tumors are represented by the C3(1)-T-antigen (C3-TAg) model, Luminal B tumors are represented by the MMTV-Neu model, and the P53 null transplant T11 line represents the newly described Claudin-low breast tumor subtype. On each of these models we have tested the therapeutic efficacy of: four chemotherapeutics (doxorubicin, carboplatin, paclitaxel, and cyclophosphamide), two chemotherapy combinations (carboplatin/paclitaxel and doxorubicin/cyclophosphamide), and three biologically targeted agents (erlotinib, lapatinib, and ABT-888, alone and combined with selected chemotherapies).

The results from individual models were as follows:

The MMTV-Neu tumors were sensitive to the single-agent chemotherapeutics carboplatin and cyclophosphamide, and cyclophosphamide dramatically increased overall survival of the MMTV-Neu mice. The targeted agents lapatinib and erlotinib were extremely effective; lapatinib produced a near complete regression in every MMTV-Neu mouse tested and both compounds lead to greatly increased survival times.

In the Claudin-low T11 line, the tumors were very sensitive to cyclophosphamide. Alone and in combination with doxorubicin, cyclophosphamide was the only chemotherapeutic able to successfully cause tumor regression in this model. None of the biological inhibitors were effective as single agents in these mice, nor were they effective in combination with chemotherapeutics other than cyclophosphamide In the C3-TAg basal-like model, carboplatin alone and in combination with other drugs caused volume reduction in some of the tumors. Erlotinib was able to cause volume reductions in a third of the treated C3-Tag tumors, which revealed a heterogeneity of response within this GEM strain. None of the single agent treatments significantly increased overall survival in these mice. Those combination treatments that were effective showed a range of responses from tumor regression to slowed progression.

Finally, we closely examined the heterogeneous responses of the C3-Tag tumors to carboplatin/paclitaxel and performed expression profiling of sensitive and resistant tumors. We identified a gene signature from these treated mouse tumors that was able to predict pathological complete response of human patients receiving multiagent taxane-containing neoadjuvant chemotherapy regimens. These results show that genomically selected GEM models can recapitulate findings seen in human tumors (like lapatinib responsiveness in HER2+ tumors and carboplatin sensitivity in basal-like tumors) and that GEM models can potentially be used to develop biomarkers and to test new drug combinations prior to their being tested in humans.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-03-03.