The efficacy of CB-103, a first-in-class transcriptional Notch inhibitor, in preclinical models of breast cancer

Abstract

BackgroundNotch signaling has been shown to mediate treatment resistance and support cancer stem cells (CSCs) in endocrine-resistant estrogen receptor positive (ER+) and triple negative breast cancers (TNBCs). The clinical development of GSIs, first generation Notch inhibitors, has been hindered by 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 doesnt induce GI toxicities noted with GSIs. There is a critical need for effective, safe, 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 elucidating the synergy of CB-103 with fulvestrant and paclitaxel in preclinical models of both hormone-refractory ER+ BC and TNBC respectively provides a novel and unique opportunity to address major unmet therapeutic needs. MethodsCB-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 GSI-resistant TNBC model HCC1187. Comparisons between groups were performed with two-sided unpaired Students t-test. One-way or two-way ANOVA followed by Tukeys post analysis was performed to analyze in vivo efficacy study results. ResultsCB-103 showed synergism with fulvestrant in ER+ cells and with 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, endocrine-resistant BC model. In a GSI-resistant TNBC model, CB-103 plus paclitaxel significantly delayed tumor growth compared to paclitaxel alone. ConclusionsOur 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.