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

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.

CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders

“…The second approach relies on the binding inhibition of N1-ICD and its transcriptional complex [43]. The most advanced example in this case is CB-103, a small molecule investigated in Notch-driven cancers [44][45][46]. CB-103 showed good efficacy in NOTCH-mutated solid tumors and an acceptable safety profile in a phase I clinical trial [47].…”

Notch signaling pathway in cancer: from mechanistic insights to targeted therapies

“… 554 In preclinical models of endocrine-resistant and TNBC, CB-103, when combined with fulvestrant or PTX, exhibits synergistic effects, effectively inhibiting the formation of breast spheroids. 555 Moellering et al introduced a hydrocarbon-stapled peptide named SAHM1, which can prevent the assembly of active transcription complexes. 556 In vivo and in vitro experiments have demonstrated that SAHM1 can treat T-ALL cells by globally suppressing Notch-activated genes.…”

Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways

“…In TNBC and T-ALL xenograft models, limantrafin markedly reduced tumor burden and prolonged survival [359]. Limantrafin in combination with paclitaxel or fulvestrant also potently inhibited mammosphere formation in breast MCF-7 and estrogen receptor positive (ER + ) cells [360]. Moreover, limantrafin synergized with paclitaxel in TNBC HCC1187 xenografts, resulting in reduced tumor growth and delayed tumor recurrence after discontinuation of treatment compared to paclitaxel alone [360].…”

“…Limantrafin in combination with paclitaxel or fulvestrant also potently inhibited mammosphere formation in breast MCF-7 and estrogen receptor positive (ER + ) cells [360]. Moreover, limantrafin synergized with paclitaxel in TNBC HCC1187 xenografts, resulting in reduced tumor growth and delayed tumor recurrence after discontinuation of treatment compared to paclitaxel alone [360]. ZLDI-8 is a novel a disintegrin and metalloproteinase 17 (ADAM-17) inhibitor, which is an enzyme involved in Notch activation and cleavage [361].…”