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

Autor: Vigolo M; Cellestia Biotech AG, 4057 Basel, Switzerland., Urech C; Cellestia Biotech AG, 4057 Basel, Switzerland., Lamy S; Cellestia Biotech AG, 4057 Basel, Switzerland., Monticone G; Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA., Zabaleta J; Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA., Hossain F; Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA., Wyczechowska D; Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA., Del Valle L; Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA., O'Regan RM; Department of Medicine, University of Rochester, Rochester, NY 14642, USA., Miele L; Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA., Lehal R; Cellestia Biotech AG, 4057 Basel, Switzerland., Majumder S; Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2023 Aug 03; Vol. 15 (15). Date of Electronic Publication: 2023 Aug 03.
DOI: 10.3390/cancers15153957
Abstrakt: 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.
Databáze: MEDLINE
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