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Poster display session

5472 - Pharmacological Activity of CB-103 - An oral pan-NOTCH inhibitor with a novel Mode of Action

Date

11 Sep 2017

Session

Poster display session

Presenters

Dirk Weber

Citation

Annals of Oncology (2017) 28 (suppl_5): v122-v141. 10.1093/annonc/mdx367

Authors

D. Weber1, R. Lehal1, V. Frismantas2, J. Bourquin2, M. Bauer1, M. Murone1, F. Radtke3

Author affiliations

  • 1 Drug Development, Cellestia Biotech AG, 4057 - Basel/CH
  • 2 Paediatric Oncology, University Children`s Hospital, 8008 - Zuerich/CH
  • 3 Research Laboratory, EPFL Lausanne, Lausanne/CH
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Resources

Abstract 5472

Background

NOTCH signalling is a developmental pathway known to play critical roles during embryonic development as well as for regulation of self-renewing tissues. Aberrant activation of NOTCH signalling leads to deregulation of the self-renewal process resulting in sustained proliferation, invasion and metastasis, all of which are hallmarks of cancer. When the NOTCH pathway is inappropriately activated by genetic lesions (over expression of NOTCH ligands/receptors, GOF mutations in NOTCH receptors as well as chromosomal translocations), it becomes a major driver for NOTCH-dependent cancers and resistance to standard of care treatment. Several therapeutic approaches have been utilized to block NOTCH signalling, e.g. a) the use of monoclonal blocking antibodies (mAbs) against NOTCH ligands and receptors and b) the use of small molecule gamma-secretase inhibitors (GSIs). Here we report the pharmacological characterization of CB-103, a first-in-class orally-active small molecule, protein-protein interaction inhibitor of the NOTCH transcriptional activation complex.

Methods

Primary pharmacodynamic (PD) studies were conducted to investigate CB-103 in relation to its desired therapeutic effect for treating advanced or metastatic haematological and solid tumour malignancies as NOTCH pathway inhibitor. Regarding the PD effect, in vitro studies demonstrated for CB-103 a dose-dependent decrease in NOTCH signalling activation with a unique mechanism compared to GSIs and mAbs. In a panel of > 120 cell lines of various malignancies CB-103 was active on a subset of 24 cancer cell lines, including different solid tumours (breast, lung, sarcomas), lymphomas and leukaemias.

Results

Moreover, CB-103 demonstrated anti-NOTCH activity in the Triple-Negative Breast Cancer HCC1187 cell line, being resistant to GSIs due to a NOTCH2 chromosomal translocation. In addition, CB-103 exhibited anti-tumour efficacy in multiple in vivo models and patients derived xenograft models.

Conclusions

Safety pharmacology and toxicology studies have been completed and revealed an excellent non-clinical safety profile of CB-103. A first-in-human Phase I/IIA clinical study in advanced solid tumours and haematological malignancies is under preparation.

Clinical trial identification

Legal entity responsible for the study

Cellestia Biotech AG

Funding

Cellestia Biotech AG

Disclosure

D. Weber: Chief Medical Officer of Cellestia, co-founder, stock ownership. R. Lehal: Chief Scientific Officer, co-founder, stock ownership. J-P. Bourquin: Medical advisory board Cellestia. M. Bauer: Chief Executive Officer, co-founder, stock ownership. M. Murone: Chief Operating Officer, co-founder, stock ownership. F. Radtke: Chairman of the Board, co-founder, stock ownership. All other authors have declared no conflicts of interest.

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