Pre-clinical Evaluation of Spliceosome and Proteasome Inhibition in Triple Negative Breast Cancer.
Praveen Sridhar, Stefanie Chan, Ying-Jie Lock, Fabio Petrocca
Boston University Department of Surgery, Boston, MA, USA
Background: Triple negative breast cancer (TNBC) comprises 15% of breast cancer diagnoses. Non-targeted cytotoxic therapies are prone to tumor resistance, metastasis, and recurrence. siRNA screening has revealed the selective necessity of proteasome and spliceosome function for the survival of TNBC cells. We explore inhibiting these pathways simultaneously, with the proteasome inhibitor Bortezomib and the splicing inhibitor E7107.
Methods: Cytotoxic doses of E7107 and Bortezomib in combination were established. Cell viability assays validated these doses across multiple TNBC subtypes. Dose escalation studies of the combination were performed in vivo using cell line derived xenografts (CDX) in mice. Efficacy was studied in vivo using both cell line and patient derived xenograft (PDX) models in mice.
Results: Cell viability was reduced by ~50% using combination therapy in 7 tested cell lines compared to treatment with DMSO. CDX mice tolerated a dose of 5mg/kg of E7107 for four consecutive days in combination with 0.4mg/kg Bortezomib given on two non-consecutive days per four day cycle. Progression free survival in ‘basal-like’ CDX mice was greater than 60 days while untreated mice experienced mortality within 24 days from the start of therapy. Significant decreases in tumor volume were seen in 80% of xenograft models, including PDX models, with pre-formed tumors.
Conclusion: Inhibition of TNBC dependency pathways may provide safe, new, and effective combinations of targeted therapy. Targeted inhibition of the proteasome and spliceosome pathways is effective in treating a subset of TNBC mouse models. These results need to be further validated in translational studies.
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