crenigacestat (LY3039478)

P1/2, N=312, Active, not recruiting, Celgene | Trial completion date: Dec 2026 --> Jan 2025

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.

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

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

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

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

Combining cisplatin with a γ-secretase inhibitor (crenigacestat) increased sensitivity and induced cell death in the less sensitive cell line, while cisplatin alone was more effective in the moderately sensitive line and sensitivity decreased with the Notch inhibitor. Additionally, the Notch ligand JAG2 had additional, protective effects reducing cell death from cisplatin exposure. In summary, we observed an inverse relationship between NOTCH1 and NOTCH3 levels and cisplatin responsiveness, overall protective effects by CAFs, and a potential link between JAG2 expression with tumor cell survival.

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.

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.

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

P1, N=18, Suspended, Fred Hutchinson Cancer Center | Trial completion date: Sep 2025 --> Sep 2026 | Trial primary completion date: Sep 2024 --> Sep 2025

Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials.

P1/2, N=312, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting

The mutation promoted migration and invasion in cell and animal models, and these effects were markedly repressed by the NOTCH inhibitor LY3039478...Furthermore, the mutation was significantly more common in metastatic lymph nodes than in other peritoneal metastases in 10 paired samples (60% vs. 20%). The study revealed that NOTCH1 mutation is probably a driver of lymph node metastasis in ovarian cancer, which offers new ideas for the treatment of ovarian cancer lymph node metastasis with NOTCH inhibitors.

Taken together, KDM4A could drive Bca progression via triggering the activation of Notch1 pathway by decreasing H3K9me3 levels, highlighting a promising therapeutic target for Bca.

Notch signaling inhibition reduces the peritumoral desmoplastic reaction in iCCA, blocking the TGF-β1 canonical pathway.

NOTCH1 is a newly identified CSC regulator. Targeting NOTCH1-cMYC signaling is a promising therapeutic strategy for ATC.

We additionally propose a pretreatment of MM cells with Bortezomib (BTZ) plus gamma secretase inhibitor (GSI) to boost NKG2D CAR efficacy in CB-NK immunotherapy for MM treatment...A pretreatment with BTZ+GSI (LY3039478) significantly enhances the ability of NKG2D CAR CB-NK cells to eradicate BTZ resistant MM cell lines in vitro, independently of low BCMA expression or even in BCMAKO-BTZ-resistant cell line... In vivo experiments show the inefficacy of irradiated CAR NK-92MI cells as therapeutic strategy in our MM model, being CAR CB-NK cells a promising immunotherapy for MM treatment. In addition, NKG2D CAR CB-NK off-the-shelf immunotherapy combined with a BTZ+GSI pretreatment regimen sensitize resistant MM cells to improve CAR-NK efficacy in MM patients.

P1, N=18, Suspended, Fred Hutchinson Cancer Center | Trial completion date: Apr 2022 --> Sep 2025 | Trial primary completion date: Apr 2022 --> Sep 2024

In addition, the drug triggered a strong immune response and blocked neovascularization in the tumor ecosystem of the HuCCT1-xenograft model without affecting the occurrence of fibrotic reactions. Therefore, although these data need further investigation, our observations confirm that Crenigacestat selectively targets NOTCH1 and that the desmoplastic response in iCCA likely plays a key role in both drug effectiveness and tumor progression.

iCCA patients with higher NOTCH1/HES1/THY1 expression have the worst prognosis, but they are more likely to benefit from Notch signaling inhibition. These findings represent the scientific rationale for testing NOTCH1 inhibitors in clinical trials, taking the first step toward precision medicine for iCCA.

Endothelial-specific Notch activation triggered LSEC maladaptation and exacerbated NASH phenotypes in an eNOS-dependent manner. Genetic and pharmacological inhibition of Notch signaling effectively restored LSEC homeostasis and ameliorated NASH progression.

Standard treatments for RRMM include daratumumab + pomalidomide + dexamethasone (DPd)andpomalidomide + bortezomib + low-dose dexamethasone (PVd)...Pts are enrolled into 3 treatment arms (non-randomized allocation; Figure): arm A, ide-cel + iberdomide (± dexamethasone), in cohorts 1 and 2 (per pt population), as maintenance therapy (subcohort a), or as both concurrent and maintenance therapy (subcohorts b and c; schedules differ); arm B, ide-cel + BMS-986405 as concurrent therapy; arm C, ide-cel + DPdor PVd as maintenance therapy...Lymphodepletion with fludarabine (30 mg/m 2 /day) and cyclosphosphamide (300 mg/m 2 /day) occurs for 3 consecutive days followed by 2 rest days before ide-cel infusion...Recruitment began in June 2021 and is ongoing in the United States and Spain. Study support bluebird bio and Celgene, a Bristol-Myers Squibb Company

We have completed accrual to a phase 1 first-in-human trial of escalating doses of BCMA targeted CAR T cells in combination with a GSI (JSMD194) for patients with relapsed or refractory multiple myeloma, and herein report results on the 18 patients accrued to this trial. From June 2018 to March 2021, 18 patients underwent leukapheresis, run-in with JSMD194, and treatment with BCMA CAR T cells. The median age was 65 years, and patients had received a median of 10 prior lines of therapy (range, 4-19). 67% of patients were refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, 72% had high-risk cytogenetic features, and 28% had extramedullary disease.

P1, N=18, Suspended, Fred Hutchinson Cancer Research Center | Trial primary completion date: Jul 2021 --> Apr 2022

P1, N=18, Suspended, Fred Hutchinson Cancer Research Center | Trial completion date: Jul 2034 --> Apr 2022 | Recruiting --> Suspended

The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016.

Methods : Primary MM cells and myeloma cell lines were treated with titrated doses of ATRA (25, 50, 100 nM), alone and in combination with the g-secretase inhibitor crenigacestat (10 nM)...After ATRA treatment, MM cells have increased susceptibility to BCMA CAR T-cell treatment in pre-clinical models vitro and in vivo, that can be increased even further by combination treatment of ATRA and g-secretase inhibitors. These data suggest the potential to improve responses (depth and durability) of immunotherapies directed against BCMA.

JAG2TANs are closely linked to IL-8-driven immune evasion microenvironment and may serve as a promising therapeutic target for the reinvigoration of anti-tumour immunity.

In the PDX model, LY3039478 significantly inhibited the Notch pathway and tumor growth to the same extent as gemcitabine. We have developed and validated a new iCCA PDX model to test in vivo the activity of LY3039478, demonstrating its inhibitory role in Notch-dependent angiogenesis. Thus, the present data provide new knowledge on Notch signaling in iCCA, and support the inhibition of the Notch cascade as a promising strategy for the treatment of this disease.