First-in-human phase 1-2A study of CB-103, an oral Protein-Protein Interaction Inhibitor targeting pan-NOTCH signalling in advanced solid tumors and blood malignancies.

García, José Manuel Pérez; Cortés, Javier; Stathis, Anastasios; Mous, Rogier; López-Miranda, Elena; Azaro, Analía; Genta, Sofia; Nuciforo, Paolo; Vivancos, Ana; Ferrarotto, Renata; Bertoni, Francesco; Rossi, Davide; Burr, Nicole Spardy; Schönborn‐Kellenberger, Oliver; Jorga, Karin; Beni, Laura; Lehal, Rajwinder; Bauer, Michael; Weber, Dirk; Garralda, Elena

doi:10.1200/jco.2018.36.15_suppl.tps2619

Cited by 9 publications

(7 citation statements)

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“…4f) are γ-secretase inhibitors (GSIs), which act unselectively to block NOTCH processing, dihydropyridine (DHP) inhibitors of NOTCH trafficking 29,30 and CB-103 22 , which appears to function at the level of NOTCH (Fig. 4) and has recently entered clinical development for treatment of NOTCH-dependent cancers 31 . As the first small molecule RBPJ inhibitor, RIN1 could be exploited for chemical genetics and therapeutic applications.…”

Section: Discussionmentioning

confidence: 99%

Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ

Hurtado

Safarova²,

Smith³

et al. 2019

Sci Rep

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NOTCH plays a pivotal role during normal development and in congenital disorders and cancer. γ-secretase inhibitors are commonly used to probe NOTCH function, but also block processing of numerous other proteins. We discovered a new class of small molecule inhibitor that disrupts the interaction between NOTCH and RBPJ, which is the main transcriptional effector of NOTCH signaling. RBPJ Inhibitor-1 ( RIN1 ) also blocked the functional interaction of RBPJ with SHARP, a scaffold protein that forms a transcriptional repressor complex with RBPJ in the absence of NOTCH signaling. RIN1 induced changes in gene expression that resembled siRNA silencing of RBPJ rather than inhibition at the level of NOTCH itself. Consistent with disruption of NOTCH signaling, RIN1 inhibited the proliferation of hematologic cancer cell lines and promoted skeletal muscle differentiation from C2C12 myoblasts. Thus, RIN1 inhibits RBPJ in its repressing and activating contexts, and can be exploited for chemical biology and therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ

Hurtado

Safarova²,

Smith³

et al. 2019

Sci Rep

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Section: Notch1mentioning

confidence: 99%

“…Recently, Cellestia Biotech AG developed a small molecule (CB-103), downregulating Notch1 target genes (c-MYC, CCND1, HES1). A phase I-IIA clinical trial (NCT03422679) is ongoing in refractory or metastatic solid tumors and hematological malignancies [61]. ACC, adenoid-cystic carcinoma; AML, acute myeloid leukemia; BC, breast cancer; BCP-ALL, B-cell precursor acute lymphoblastic leukemia; ChT, chemotherapy; CMML, chronic myelomonocytic leukemia; CRC, colo-rectal cancer; DSRP, drug sensitivity and resistance profiling; HCC, hepatocellular carcinoma; HR-MDS, high-risk myelodysplastic syndrome; LBL, lymphoblastic lymphoma; MGT, malignant glomus tumor; MM, multiple myeloma; MPAL, mixed phenotype acute leukemia; NHL, non-Hodgkin lymphoma; R/R, relapsed/refractory; SLL, small lymphocytic lymphoma; T-ALL, T-cell acute lymphoblastic leukemia; TKI, tyrosine-kinase inhibitors.…”

Section: Notch1mentioning

confidence: 99%

Modern treatment approaches to adult acute T-lymphoblastic and myeloid/T-lymphoblastic leukemia: from current standards to precision medicine

Leoncin

Starza

Roti

et al. 2022

Current Opinion in Oncology

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Purpose of reviewTo review the most recent advancements in the management of adult T-cell acute lymphoblastic leukemia (T-ALL), we summarize insights into molecular diagnostics, immunotherapy, targeted therapy and new techniques of drug sensitivity profiling that may support further therapeutic progress in T-ALL subsets.Recent findingsWith current induction/consolidation chemotherapy and/or risk-oriented allogeneic stem cell transplantation programs up to 95% adult T-ALL patients achieve a remission and >50% (up to 80% in adolescents and young adults) are cured. The group of patients who fail upfront therapy, between 25% and 40%, is enriched in high-risk characteristics (unfavorable genetics, persistent minimal residual disease) and represents the ideal setting for the study of molecular mechanisms of disease resistance, and consequently explore novel ways of restoration of drug sensitivity and assess patient/subset-specific patterns of drug vulnerability to targeting agents, immunotherapy and cell therapy.SummaryThe emerging evidence supports the contention that precision medicine may soon allow valuable therapeutic chances to adult patients with high-risk T-ALL. The ongoing challenge is to identify the best way to integrate all these new data into the therapeutic path of newly diagnosed patients, with a view to optimize the individual treatment plan and increase the cure rate.

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“…Furthermore, the aggressive TNBC cell line HCC1187, which harbours a chromosomal translocation in the Notch 2 gene, rendering it resistant to GSIs, demonstrated sensitivity to CB-103, suggesting that it may be a more suitable treatment strategy for Notch-addicted tumours with such genotypes. A first-in-man Phase I/IIa multicentre open-label dose-escalation trial with an expansion study to determine preliminary antitumour efficacy is ongoing currently (NCT034226790), aiming to recruit 165 patients with advanced, refractory or metastatic solid tumours (breast, colorectal, cholangiocarcinoma and sarcoma) or haematological malignancies for whom no standard therapy exists [ 200 ].…”

Section: Inhibiting the Notch Pathway With Molecular-targeted Thermentioning

confidence: 99%

Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

Moore

Annett

McClements

et al. 2020

Cells

103

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Evolutionarily conserved Notch plays a critical role in embryonic development and cellular self-renewal. It has both tumour suppressor and oncogenic activity, the latter of which is widely described. Notch-activating mutations are associated with haematological malignancies and several solid tumours including breast, lung and adenoid cystic carcinoma. Moreover, upregulation of Notch receptors and ligands and aberrant Notch signalling is frequently observed in cancer. It is involved in cancer hallmarks including proliferation, survival, migration, angiogenesis, cancer stem cell renewal, metastasis and drug resistance. It is a key component of cell-to-cell interactions between cancer cells and cells of the tumour microenvironment, such as endothelial cells, immune cells and fibroblasts. Notch displays diverse crosstalk with many other oncogenic signalling pathways, and may drive acquired resistance to targeted therapies as well as resistance to standard chemo/radiation therapy. The past 10 years have seen the emergence of different classes of drugs therapeutically targeting Notch including receptor/ligand antibodies, gamma secretase inhibitors (GSI) and most recently, the development of Notch transcription complex inhibitors. It is an exciting time for Notch research with over 70 cancer clinical trials registered and the first-ever Phase III trial of a Notch GSI, nirogacestat, currently at the recruitment stage.

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First-in-human phase 1-2A study of CB-103, an oral Protein-Protein Interaction Inhibitor targeting pan-NOTCH signalling in advanced solid tumors and blood malignancies.

Cited by 9 publications

References 0 publications

Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ

Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ

Modern treatment approaches to adult acute T-lymphoblastic and myeloid/T-lymphoblastic leukemia: from current standards to precision medicine

Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

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