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.

Moreover, these identified water components were present at levels comparable to other regions with high female cancer prevalence, suggesting that the potential risk of these components may not be exclusive to the study region. Together, multiple levels of evidence suggested that long-term co-exposures to source water estrogenic components may be important to the development of breast, ovarian, and uterus cancers.

*Inverse variance method, no transformation, 0.5 continuity correction. ORR: CR + PR; DCR: CR + PR + SD Conclusions AL101 showed acceptable safety and tolerability in ACC pts with Notchmut and a response rate comparable to pooled estimates for available therapies in pts regardless of Notch status.

Ni included AL101, a gamma-secretase inhibitor, or OMP-52M51, an antibody targeting N1...The efficacy of Ni compares favorably with efficacy of systemic therapies administered prior to Ni. The limited PFS and high rate of tumor progression on non-target lesions suggests Ni combination therapy may be necessary to address ACC heterogeneity.

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

P2, N=23, Not yet recruiting, Stanford University

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

P2, N=53, Active, not recruiting, SpringWorks Therapeutics, Inc. | Recruiting --> Active, not recruiting

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, N=30, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2023 --> Oct 2026 | Trial primary completion date: Oct 2023 --> Oct 2026

No abstract available

P2, N=40, Not yet recruiting, M.D. Anderson Cancer Center

Up to 40% of DLBCL patients display refractory disease or relapse after standard chemotherapy treatment (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), leading to significant morbidity and mortality. Targeting CHOP-resistant DLBCL tumors with the Phase 3 clinical trial molecules nirogacestat, a selective g-secretase inhibitor, and ipatasertib, a pan-AKT inhibitor, synergistically promotes DLBCL death. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in KLHL6- or NOTCH2-mutated DLBCL.

The combination of tec + niro yielded response rates of 57–92% across 3 dose levels assessed. This initial experience with tec + niro provides insights on the combination of BCMA-directed therapies with a gamma secretase inhibitor. Phase I, Bispecific, Multiple myeloma, B-cell maturation antigen

Despite utilizing a belamaf dose and schedule that are expected to have limited activity as a monotherapy, low- dose belamaf + nirogacestat demonstrated an encouraging ORR with a substantial reduction of high-grade ocular events, indicating an increase in BCMA target density by nirogacestat. Furthermore, the efficacy and safety data from the monotherapy arm were consistent with DREAMM-2, DREAMM-3, and real-world evidence observed to date. These data support ongoing exploration in DREAMM-5 of belamaf + nirogacestat + standard of care agents in patients with RRMM.

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.

Moreover, DAPT promoted the migration of H1299 cells by increasing the activity of Rac1 through the non-canonical Notch pathway. Taken together, these results indicate that the expression of p53 protein in lung cancer cells regulates the effect of DAPT on cell migration by modulating the activation of Rac1, suggesting that p53 may affect the therapeutic effects of Notch inhibitors in lung cancer patients.