Abstract
Abstract The Notch signaling pathway plays a central role in cellular differentiation, growth and stem cell maintenance. Expression and activation of Notch pathway receptors and ligands have differential outcomes depending on the tissue, localization and cell type. When Notch pathway is aberrantly activated by genetic lesions, it can be a major driver for Notch-dependent cancers and can cause resistance to standard of care treatment. We and others have shown that in Estrogen Receptor (ER)-positive breast cancers, estrogen deprivation caused by endocrine therapy results in Notch1 and Notch4 activation. In turn, Notch1 stimulated ER-dependent transcription in the absence of estrogen, causing endocrine resistance. Combinations of Notch inhibitors and endocrine therapy are effective in preclinical models of ER-positive breast cancer and have shown promising signals in early clinical trials. Cellestia's lead development candidate CB-103 is a small molecule, first-in-class, oral pan-Notch inhibitor. CB-103 selectively blocks Notch pathway activation-related gene transcription through binding to a Notch specific protein in the transcription factor complex. The blockade occurs by protein-protein interaction inhibition with a binding site critical for the assembly of the Notch transcription complex. This is a unique mode of action, which allows blocking Notch signaling regardless of the genetic lesions which have activated the pathway. We have performed mammosphere assays to test the potency and efficacy of this compound on stem cell ability to form sphere. We used two different doses of CB-103; either alone or in combination with a fixed dose of Fulvestrant (30nM), a SERD, in our mammosphere assays. Two different ER+ luminal,endocrine resistant cell lines were tested and compared with their parental controls. From our data, it's apparent that there is a synergistic effect when using CB-103 in combination with Fulvestrant. It's also evident that the efficacy of CB-103 is maximal maximizes at the lowest concentration tested in our assays. The combination was effective in 3 out of 4 models. However, the effect of CB-103 on MCF7-TAMR either as a single agent or in combination was not statistically significant. Cellestia has received regulatory approval to start clinical development with CB-103 in a first-in-human study Phase l – lla study investigating safety (Ph l) and preliminary single agent efficacy (Ph lla) of CB-103 in patients with advanced solid cancers and haematological malignancies. Our data support the notion of testing this agent in ER-positive breast cancer in combination with SERDs. Citation Format: Majumder S, Crabtree J, Hossain F, Murone M, Lehal R, Miele L. A novel, first in class Notch transcriptional inhibitor, CB-103 has activity on luminal breast cancer stem cells in combination with fulvestrant [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-07-05.
Published Version
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