P2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Active, not recruiting

Here we report the cryo-electron microscopy structures of human γ-secretase bound individually to five clinically tested GSIs (RO4929097, crenigacestat, BMS906024, nirogacestat and MK-0752) at overall resolutions of 2.4-3.0 Å. The size and shape of the binding pocket are induced by the bound GSI. Analysis of these structural features suggest strategies for modification of the GSI with improved inhibition potency.

The expression of GINS1 enhances the expression of Notch1 and Notch3 receptors, and then phosphorylates and activates the downstream PI3K/AKT/mTORC1 signaling pathway to enhance the glycolysis, proliferation and metastasis of LUAD cells.

Our findings support the Notch pathway as a druggable target in MPNSTs. Our identification of PRC2-regulated genes and pathways could result in more novel therapeutic approaches.

Furthermore, High-risk patients tended to be more sensitive to thalidomide, MK-0752, and BRD-K17060750. The novel platelets-related genes signature we identified could be used for prognosis and treatment prediction in GC.

P1, N=22, Recruiting, Immunome, Inc. | Not yet recruiting --> Recruiting

P1, N=9, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=30 --> 9

P1, N=22, Not yet recruiting, Immunome, Inc.

P1, N=14, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

The spectrum of pathogenic variants in the BRCA1/2 genes in La Rioja is similar to that in other Spanish regions, with some unique characteristics. The pathogenic c.6024dupG variant in the BRCA2 gene was detected in a large number of families and could have a founding effect in the Ebro riverside areas in the regions of La Rioja and Navarra.

The hCAFs/iCCA cross-talk is a new target for reducing cancer progression with drugs such as Crenigacestat.

P2/3, N=192, Active, not recruiting, Immunome, Inc. | Trial completion date: Feb 2025 --> Oct 2026 | Trial primary completion date: Jan 2025 --> Oct 2025

P1, N=47, Terminated, Celgene | N=160 --> 47 | Active, not recruiting --> Terminated; Slow accrual

DBZ ameliorated DOX-induced cardiotoxicity, evidenced by reducing the cardiac injury biomarkers, improving cardiac histopathological changes, correcting antioxidant levels, and reducing inflammatory and apoptotic proteins. Our study indicates the protective effect of Notch inhibitor against DOX-induced cardiotoxicity.

P3, N=142, Active, not recruiting, SpringWorks Therapeutics, Inc. | Trial completion date: Dec 2023 --> Dec 2024

P1, N=14, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

Celastrol inhibits the function of B16-F10 cells by inhibiting the PI3K/AKT/mTOR cellular pathway and regulating the expression of downstream HIF-α mRNA.

P2/3, N=192, Active, not recruiting, Ayala Pharmaceuticals, Inc, | Recruiting --> Active, not recruiting

P1, N=160, Active, not recruiting, Celgene | Trial completion date: May 2025 --> Aug 2024 | Trial primary completion date: May 2025 --> Aug 2024

P2, N=18, Terminated, Ayala Pharmaceuticals, Inc, | N=67 --> 18 | Active, not recruiting --> Terminated; Sponsor's decision

P2, N=17, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

P2, N=87, Completed, Ayala Pharmaceuticals, Inc, | Active, not recruiting --> Completed

Our findings strongly indicate that c-Fos plays a crucial role in the promotion of cell proliferation through Notch1 signaling in KSHV-infected cells. Furthermore, our results suggest that the inhibition of expression of key viral pathogenic proteins is likely involved in this process.

P1, N=160, Active, not recruiting, Celgene | Trial completion date: Apr 2024 --> May 2025 | Trial primary completion date: Apr 2024 --> May 2025

P1, N=11, Completed, Eli Lilly and Company | Active, not recruiting --> Completed | Trial completion date: Oct 2023 --> May 2023

P1, N=19, Terminated, Fred Hutchinson Cancer Center | Active, not recruiting --> Terminated; Closed per SRC Low Accrual Policy

P1, N=19, Active, not recruiting, Fred Hutchinson Cancer Center | Suspended --> Active, not recruiting

P2, N=53, Active, not recruiting, SpringWorks Therapeutics, Inc.

P2, N=40, Not yet recruiting, M.D. Anderson Cancer Center | Initiation date: Oct 2023 --> Oct 2024

No abstract available

In a phase I, first-in-human clinical trial (n=18; relapsed/refractory MM) combining the GSI, crenigacestat, with anti-BCMA CAR T-cell therapy (FCARH143), we recently demonstrated that plasma cell BCMA antibody-binding capacity increased a median of 12-fold among 17/18 (94%) of participants after they received a 5-day GSI "run-in" (25 mg orally administered QOD for 3 doses) [Cowan AJ, et al...Accessibility of CD38, the target of daratumumab, was significantly increased in B cells, and SLAMF7, the target of elotuzumab, was significantly increased in plasma cells... BCMA cleavage from myeloma cells' surface is a putative resistance mechanism to BCMA-targeting immunotherapy. This study assessed the single-cell transcriptome and chromatin accessibility in the bone marrow environment of 16 patients given GSI monotherapy to ultimately enhance the efficacy of subsequent anti-BCMA CAR T-cell therapy. We found that prior BCMA-targeted therapy resulted in reduced chromatin accessibility within the BCMA epigenome.

Our novel findings indicate a therapeutic potential of MK0752 in HPV-positive HNSCC. Indeed, further investigation is needed for validation of our results and for the assessment of the mechanistic background.

P1/2, N=36, Recruiting, Hellenic Society of Hematology | Not yet recruiting --> Recruiting

P2, N=17, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Dec 2023

Therefore, we have focused on combination therapy using a γ-secretase inhibitor LY411575 that would enhance the efficacy of SAHA by blocking the canonical Notch pathway mediated via its intracellular domain. Besides, it also mediates autophagy-independent cell death and diminishes the expression of inflammatory cytokines, along with the downregulation in the expression of the Notch downstream genes and mesenchymal markers. Altogether, our study provides a mechanistic basis for combating EMT potentiated by SAHA, which could be utilized as a rational strategy for the treatment of solid tumors, especially triple-negative breast cancer.

Notch pathway inhibition sensitizes PDAC tumors to RT in vivo, but not in vitro, suggesting involvement of the TME. Indeed, co-culture with PDAC cells stimulates notch signaling in fibroblasts, suggesting non-cell autonomous mechanisms mediating fibrosis in the TME driving radioresistance. Future studies will determine if ADAM10 inhibition targeting PDAC cells and/or gamma secretase inhibition targeting the TME enhances radiation sensitivity in vivo by blocking fibroblast Notch signaling.

Furthermore, the NOTCH2-mediated tumorigenesis was mostly reversed after NF-κB inhibitor Bay11-7082 treatment. These findings identified the NOTCH2 P2113S mutation in ovarian carcinogenesis, and NOTCH2 P2113S is a potential target in treating OC.

We also demonstrated that the combination of LAQ and a Notch signaling pathway inhibitor significantly inhibited the growth of tumor cells in vivo using an allograft tumor model. This study indicates that inhibition of the Notch signaling pathway provides a valuable strategy for enhancing solid tumor sensitivity to LAQ.

GODDESS was found to be reliable, valid, responsive, and interpretable as a clinical trial endpoint in the pooled sample of DT/AF patients. Estimated MCTs can be used to define responders and assess group-level differences in future, unblinded, efficacy analyses.

Notch pathway inhibition sensitizes PDAC tumors to RT in vivo , but not in vitro , suggesting involvement of the TME. Indeed, co-culture with PDAC cells stimulates notch signaling in fibroblasts, suggesting non-cell autonomous mechanisms mediating fibrosis in the TME driving radioresistance. Future studies will determine if ADAM10 inhibition targeting PDAC cells and/or gamma secretase inhibition targeting the TME enhances radiation sensitivity in vivo by blocking fibroblast Notch signaling.

To sum up, we revealed previously unrecognized action mechanisms of CD51 on HCC progression and uncovered the underlying cause of cilengitide treatment failure and supported the translational prospects of combined CD51-targeted therapy in the clinic.