The Efficacy of CB-103, a First-in-Class Transcriptional Notch Inhibitor, in Preclinical Models of Breast Cancer

SIMPLE SUMMARY: Notch signaling has been shown to mediate treatment resistance and support cancer stem cells (CSC) in luminal endocrine-resistant and triple negative breast cancers (TNBCs). The clinical development of GSIs, first-generation Notch inhibitors, has been hindered by a lack of Notch specificity and dose-limiting toxicity. Here, we describe the safety and efficacy of a first-in-class, clinical-stage orally-available-small-molecule-pan-Notch inhibitor, CB-103. Due to its unique mode of action, CB-103 does not induce GI toxicities noted with GSIs. There is a critical need for effective, safe, and targeted therapies for patients with endocrine-refractory metastatic breast cancer. Recently approved targeted therapies for TNBC are only effective for a subset of patients. Moreover, GSI-resistant, constitutively activating Notch1 or Notch2 mutations are observed in ~10% of TNBC. Our study elucidates the synergy of CB-103 with fulvestrant and paclitaxel in preclinical models of hormone-refractory ER+ breast cancer and TNBC, respectively, providing a novel and unique opportunity to address major unmet therapeutic needs. ABSTRACT: Background: The efficacy of CB-103 was evaluated in preclinical models of both ER+ and TNBC. Furthermore, the therapeutic efficacy of combining CB-103 with fulvestrant in ER+ BC and paclitaxel in TNBC was determined. Methods: CB-103 was screened in combination with a panel of anti-neoplastic drugs. We evaluated the anti-tumor activity of CB-103 with fulvestrant in ESR1-mutant (Y537S), endocrine-resistant BC xenografts. In the same model, we examined anti-CSC activity in mammosphere formation assays for CB-103 alone or in combination with fulvestrant or palbociclib. We also evaluated the effect of CB-103 plus paclitaxel on primary tumors and CSC in a GSI-resistant TNBC model HCC1187. Comparisons between groups were performed with a two-sided unpaired Students’ t-test. A one-way or two-way ANOVA followed by Tukey’s post-analysis was performed to analyze the in vivo efficacy study results. The results: CB-103 showed synergism with fulvestrant in ER+ cells and paclitaxel in TNBC cells. CB-103 combined with fulvestrant or paclitaxel potently inhibited mammosphere formation in both models. Combination of CB-103 and fulvestrant significantly reduced tumor volume in an ESR1-mutant, the endocrine-resistant BC model. In a GSI-resistant TNBC model, CB-103 plus paclitaxel significantly delayed tumor growth compared to paclitaxel alone. Conclusion: our data indicate that CB-103 is an attractive candidate for clinical investigation in endocrine-resistant, recurrent breast cancers with biomarker-confirmed Notch activity in combination with SERDs and/or CDKis and in TNBCs with biomarker-confirmed Notch activity in combination with taxane-containing chemotherapy regimens.