CB‐103: A novel CSL‐NICD inhibitor for the treatment of NOTCH‐driven T‐cell acute lymphoblastic leukemia: A case report of complete clinical response in a patient with relapsed and refractory T‐ALL

Medinger, Michael; Junker, Till; Heim, Dominik; Tzankov, Alexandar; Jermann, Philip; Bobadilla, María; Vigolo, Michele; Lehal, Rajwinder; Vogl, Florian D.; Bauer, Michael; Passweg, Jakob

doi:10.1002/jha2.510

Cited by 14 publications

(9 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Clinical trials of pharmacologics to control calcification are ongoing (NCT05646381, NCT03305536, NCT04055883, NCT04429035) [115 ▪ ,136–139]. Inhibitors of Notch signalling pathway (CB-103 and crenigacestat), which inhibit in-vitro VIC osteogenic differentiation, have passed the first phase of clinical trials and future studies will determine their efficacy [140 ▪ ,141,142]. Anti-inflammatory therapies are also of interest such as agents modulating the IL-6 signalling pathway (e.g.…”

Section: Translation Into Therapeuticsmentioning

confidence: 99%

Genetics of aortic valve disease

Ackah

Yasuhara

Garg

2023

Current Opinion in Cardiology

View full text Add to dashboard Cite

Purpose of reviewAortic valve disease is a leading global cause of morbidity and mortality, posing an increasing burden on society. Advances in next-generation technologies and disease models over the last decade have further delineated the genetic and molecular factors that might be exploited in development of therapeutics for affected patients. This review describes several advances in the molecular and genetic understanding of AVD, focusing on bicuspid aortic valve (BAV) and calcific aortic valve disease (CAVD).Recent findingsGenomic studies have identified a myriad of genes implicated in the development of BAV, including NOTCH1, SMAD6 and ADAMTS19, along with members of the GATA and ROBO gene families. Similarly, several genes associated with the initiation and progression of CAVD, including NOTCH1, LPA, PALMD, IL6 and FADS1/2, serve as the launching point for emerging clinical trials.SummaryThese new insights into the genetic contributors of AVD have offered new avenues for translational disease investigation, bridging molecular discoveries to emergent pharmacotherapeutic options. Future studies aimed at uncovering new genetic associations and further defining implicated molecular pathways are fuelling the new wave of drug discovery.

show abstract

Section: Translation Into Therapeuticsmentioning

confidence: 99%

Genetics of aortic valve disease

Ackah

Yasuhara

Garg

2023

Current Opinion in Cardiology

View full text Add to dashboard Cite

show abstract

“…A phase 2 clinical trial of AL101, a different gamma secretase inhibitor, is currently underway (NCT03691207) with promising preliminary results [ 53 , 93 ]. CB-103, a pan-NOTCH inhibitor which works further downstream at the transcriptional level, was recently tested in multiple solid tumors in a phase 1 trial [ 94 , 95 ]. Among R/M ACC patients, a median PFS of 21.7 weeks was achieved, including radiologically confirmed SD >6 months in multiple ACC patients with activating NOTCH mutations [ 95 ].…”

Section: Emerging Therapies For Accmentioning

confidence: 99%

Approaches to the Management of Metastatic Adenoid Cystic Carcinoma

Lee

Wai

Chan

et al. 2022

Cancers

View full text Add to dashboard Cite

High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents — cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR — in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC.

show abstract

“…The small molecule inhibitor CB-103, which targets the Notch transcriptional complex [ 43 ], proved to be well-tolerated in a phase I study of adenoid cystic carcinoma. While showing limited antitumour activity as monotherapy [ 44 ], a complete clinical response in a patient with relapsed and refractory T-ALL was achieved when used in combination with ongoing therapy [ 45 ]. Notch receptor- or ligand-specific antibodies represent another potential therapy avenue, which have the advantage of blocking the functions of individual receptors or ligands, thus avoiding potential safety issues associated with pan-Notch inhibition[ 41 , 42 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of a Notch transcriptomic signature for breast cancer

Braune,

Geist,

Tang

et al. 2024

Breast Cancer Res

View full text Add to dashboard Cite

Background Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools to measure the level of Notch signalling in breast cancer subtypes and in response to systemic therapy are largely lacking. A transcriptomic signature of Notch signalling would be warranted, for example to monitor the effects of future Notch-targeting therapies and to learn whether altered Notch signalling is an off-target effect of current breast cancer therapies. In this report, we have established such a classifier. Methods To generate the signature, we first identified Notch-regulated genes from six basal-like breast cancer cell lines subjected to elevated or reduced Notch signalling by culturing on immobilized Notch ligand Jagged1 or blockade of Notch by γ-secretase inhibitors, respectively. From this cadre of Notch-regulated genes, we developed candidate transcriptomic signatures that were trained on a breast cancer patient dataset (the TCGA-BRCA cohort) and a broader breast cancer cell line cohort and sought to validate in independent datasets. Results An optimal 20-gene transcriptomic signature was selected. We validated the signature on two independent patient datasets (METABRIC and Oslo2), and it showed an improved coherence score and tumour specificity compared with previously published signatures. Furthermore, the signature score was particularly high for basal-like breast cancer, indicating an enhanced level of Notch signalling in this subtype. The signature score was increased after neoadjuvant treatment in the PROMIX and BEAUTY patient cohorts, and a lower signature score generally correlated with better clinical outcome. Conclusions The 20-gene transcriptional signature will be a valuable tool to evaluate the response of future Notch-targeting therapies for breast cancer, to learn about potential effects on Notch signalling from conventional breast cancer therapies and to better stratify patients for therapy considerations.

show abstract

CB‐103: A novel CSL‐NICD inhibitor for the treatment of NOTCH‐driven T‐cell acute lymphoblastic leukemia: A case report of complete clinical response in a patient with relapsed and refractory T‐ALL

Cited by 14 publications

References 14 publications

Genetics of aortic valve disease

Genetics of aortic valve disease

Approaches to the Management of Metastatic Adenoid Cystic Carcinoma

Identification of a Notch transcriptomic signature for breast cancer

Contact Info

Product

Resources

About