P2/3, N=150, Active, not recruiting, Compass Therapeutics | Recruiting --> Active, not recruiting

P1/2, N=50, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=84, Active, not recruiting, Compass Therapeutics | Recruiting --> Active, not recruiting

P2, N=84, Recruiting, Compass Therapeutics | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

P2/3, N=150, Recruiting, Compass Therapeutics | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Jul 2025

P1/2, N=92, Active, not recruiting, Handok Inc. | Recruiting --> Active, not recruiting | Phase classification: P1b/2a --> P1/2 | Trial primary completion date: Aug 2024 --> Nov 2023

Systemic chemotherapy usually begins with gemcitabine, platinum agents, and a checkpoint inhibitor followed by 5-FU and oxaliplatin, irinotecan or a taxane...150 patients will be randomized in a 2:1 ratio to receive either CTX-009 plus paclitaxel or paclitaxel alone...Key secondary objectives include overall survival, progression-free survival, and duration of response. Clinical trial information: 251040.

Up to 30 patients will be enrolled to each CRC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort A1) or in combination with irinotecan (180 mg/m2 on Days 1 and 15 of a 28-day cycle, Cohort A2). Secondary efficacy endpoints include overall survival, time to response, disease control rate, duration of response, and the relationship between antitumor activity of navicixizumab and Xerna TME Panel biomarker subtypes. Clinical trial information: NCT05453825.

Eligible TNBC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 4 prior lines of standard therapy for metastatic disease, including immunotherapy (for PD-L1 positive TNBC patients), and sacituzumab govitecan...Up to 30 patients will be enrolled to each TNBC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort C1) or in combination with paclitaxel (80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle) (Cohort C2)...Cohort continuation and future evaluation decisions will be guided by the boundaries identified by a sequential monitoring procedure. Secondary efficacy endpoints include overall survival, time to response, disease control rate, duration of response, and the relationship between antitumor activity of navicixizumab and Xerna TME Panel™ biomarker subtypes.

P2, N=84, Not yet recruiting, Compass Therapeutics

P1b | N=44 | NCT03030287 | Sponsor: OncoMed Pharmaceuticals, Inc | "Navicixizumab plus paclitaxel showed promising and durable clinical activity in a heavily pretreated patient population regardless of prior treatment (median of four prior therapies) Overall response rate (ORR) across all evaluable patients: 43% (19/44), ORR in patients previously treated with bevacizumab (Avastin®): 33% (10/30), ORR in patients previously treated with a PARP inhibitor: 45% (9/20),11 of 19 patients with partial or complete response had progressive disease as best response to immediate prior therapy. Median duration of response: 6 months. B+ classification showed enrichment of patients with tumor response. ORR in B+ vs. B- patients: 62% (8/13) vs. 25% (5/20), Best response of progressive disease in B+ vs. B- patients: 0% (0/13) vs. 30% (6/20), Median progression-free survival in B+ vs. B- patients: 9.2 months vs. 3.9 months."

P1/2, N=144, Recruiting, Jason J. Luke, MD | Trial completion date: Nov 2021 --> Jun 2024 | Trial primary completion date: Nov 2021 --> Mar 2023

MiR-3648 may play a critical role in EA pathogenesis. The novel 4-gene signature may serve as a prognostic tool to manage patients with EA.

P3, N=400, Ongoing, OncXerna Therapeutics, Inc.

The data indicate that intratumoral variation in NOTCH1 expression can lead to upregulation of DLL4 expression within the microtumor and enhancement of microtumor invasiveness. Overall, our results reveal a novel mechanism of heterogeneity mediated invasiveness through intratumoral variation of gene expression.

Further, the GSIs (DAPT, LY-411575, RO4929097, MK0752, etc.) suffer from poor bioavailability and off-target side effects such as diarrhea, suppression of lymphopoiesis, headache, hypertension, fatigue, and ventricular dysfunctions. The delivery system is designed to deliver the drug cargo precisely to TNBCs through its DR-5 receptors and hence expected to reduce the off-target side effects of GSIs. Further, DLL4 mAb and GSIs are expected to act synergistically to block the Notch signal mediated BCSCs proliferation, differentiation, and metastasis.

The gene-drug interaction network then indicated that ESM1 inhibitors, such as cisplatin, might serve as potential drugs for the therapy of ACC. Collectively, the results asserted that ESM1 and related regulators might act as underlying prognostic biomarkers or novel therapeutic targets for ACC.

In conclusion, knockdown of GRB7 in ovarian cancer cells is an attractive potential therapeutic target for the suppression of angiogenesis in ovarian cancer. GRB7 may regulate angiogenesis through VEGFA/VEGFR2 signaling and its downstream pathways.

Together, these data show that MEF2C is an oncogenic driver of ETP-ALL, and ectopic expression of MEF2C negatively affects steroid sensitivity. Specific targeting of only those HDACs that promote MEF2C activity may provide new therapeutic options in ETP-ALL by inhibiting MEF2C function and enhancing steroid sensitivity.

These data suggests that our DLL4 culture system, along with feeder-free NK cell differentiation is a unique combination that is able to give rise to high number of pure NK cell population with high cytotoxic potential. These results lay a foundation towards an easier approach to NK cell therapy for effective treatment of cancers and viral infections, which will be developed in collaboration with Smart Immune Inc.

After KEGG and STRING-GO analysis, oxidative stress, ER stress, cell adhesion, and apoptosis genes were up-regulated with H. pylori infection but down-regulated with kimchi, whereas tissue regeneration, cellular anti-oxidative response, and anti-inflammation genes were reversely regulated with kimchi (p<0.01). Conclusively, transcriptomes of H. pylori plus kimchi showed significant biological actions.

This pilot study shows that DLL4 is overexpressed in endometrial cancer cells, vasculature and is also elevated in the plasma of a fraction of patients before surgery. The percentage of DLL4+ vessels in the penetrating sample ranged from 10-70%, indicating a large difference in the quality of angiogenesis produced between the endometrial tumors of the same histological type and differentiation.

EERAC might suppress CRC through targeting Notch/DLL4/Hes1 pathway and inhibiting angiogenesis in tumors. This study might provide novel thought for the prevention and therapy of CRC through targeting Notch/DLL4/Hes1.

We further show that basp1 promotes angiogenesis by upregulating β-catenin gene and the Dll4/Notch1 signaling pathway. These results, to the best of our knowledge, provide the first in vivo evidence to indicate the role of Basp1 as an angiogenesis-regulating gene and opens the potential therapeutic avenues for a wide variety of systemic angiogenesis-dependent diseases.

The levels of circPVT1 were obviously related to cumulative relapse rate and 5-year survival rate. In conclusion, our study reveals that circPVT1 participates in the progression of T-ALL through the miR-30e/DLL4 pathway and might represent a potential therapeutic target for T-ALL treatment.

NOTCH2/3 and DLL4 are potential drivers of Notch signaling in BCa, indicating that Notch and associated pathways play an essential role in the progression and prognosis of BCa through directly modulating immune cells or through interaction with cell cycle and EMT.

We show that no single growth factor-ligand pair universally induces DIPG cell invasion. However, our results reveal a potential to create a composite of cytokines or anti-cytokines to modulate DIPG cell invasion.

The results showed that TSE1 had more potent cell growth inhibitory effects on ovarian cancer OVCAR-3 and A2780/CP70 cells than cisplatin and was lower in cytotoxicity to normal ovarian IOSE-364 cells...Combination treatment of TSE1 with the Notch1 signaling inhibitor tert-butyl (2S)-2-&lsqb;&lsqb;(2S)-2-&lsqb;&lsqb;2-(3,5-difluorophenyl)acetyl]amino]propanoyl]amino]-2-phenylacetate (DAPT), or the Akt signaling inhibitor wortmannin, showed a stronger inhibition toward HIF-1α activation compared with single compound treatment. Taken together, TSE1 might be a potential candidate compound for improving platinum-resistant ovarian cancer treatment via Dll4/Jagged1-Notch1-Akt-HIF-1α axis.

Thus, these findings highlight the antitumour impact of simultaneous suppression of c-Met and VEGFR2 signalling in GAC and its potential to enhance nanoparticle paclitaxel response. This therapeutic approach might lead to a clinically beneficial combination to increase GAC patients' survival.

Amongst them, crizotinib, foretinib, and Pha665752 exhibited the strongest radiosensitizing effect. Kinase activity profiling showed an association of crizotinib resistance with compensatory PI3K/AKT and MAP kinase signaling. Overall, our results indicate that c-MET is conferring radioresistance in HNSCC through modulation of intracellular kinase signaling and stem-like features.

Furthermore, an enhanced interaction between p53 and Sp1 was observed in TS. In NSCLC cells, high levels of active Notch1 can promote a reversible shift of driver dependence from EGFR to Notch1, leading to resistance to EGFR inhibitors.

The γ secretase inhibitors, BMS-708163, GSI-IX, PF-3084014, and RO4929097 abrogated the enzalutamide resistance by inhibiting Notch1 or/and Notch4 in vitro, with GSI-IX and RO4929097 being more effective than BMS-708163 and PF-3084014 in reliving bone metastasis in vivo. In conclusion, the Notch1 and Notch4 inhibitors GSI-IX and RO4929097 are promising therapeutic agents for the treatment of CRPC.

In conclusion, our results indicated that neuritin is involved in angiogenesis and may play a role in angiogenesis through the Notch signaling pathway. This study provides a theoretical basis for clinical anti-angiogenesis therapy.

Consequently, down-regulation of CRNDE could down-regulate tumour volume, simultaneously down-regulate the expression of CD163 and CD31 in tissues, decrease the expression of key proteins (including JAK-1, STAT-6, p-STAT6 and p-AKT1), and down-regulate the expression of key angiogenesis-related proteins (including VEGF, Notch1, Dll4 and VEGFR2). In this study, we found that CENDE could indirectly regulate tumour angiogenesis by promoting M2 polarization of macrophages, which is also one of the mechanisms of microenvironmental immune regulation in liver cancer.

Moreover, genes such as NOTCH1, PRKACB, WNT7B, and WNT5B were involved in multiple signaling pathways, displaying greater growth inhibition. In conclusion, the findings suggest that MS13 may demonstrate anti-cancer effects through modulating key canonical pathways that enhances tumor-suppressive and inhibits oncogenic genes, indicating a potential therapeutic agent for AIPC.

The results indicated that foretinib might have the therapeutic potential against human GBM which deserve further investigation.

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov).