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Combination Study of BMS-754807 and Erbitux in Subjects With Advanced or Metastatic Solid Tumors

ABSTRACT: The study is expected to identify a safe dose of BMS-754807 to be given in combination with a standard dose of cetuximab and the recommended dose or dose range for Phase II studies. The study is also intended to collect first data on the effects of the combination of BMS-754807 with cetuximab on tumors of patients with colorectal cancer or squamous cell cancer of the head and neck for whom cetuximab-containing therapies have not been effective

DISEASE(S): Neoplasm Metastasis,Colorectal Cancer,Head And Neck Cancer

PROVIDER: 2072782 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Single-cell Sequencing Analysis of Head and Neck Squamous Cell Carcinoma

Project description:To investigate the mechanism of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC), we performed single-cell RNA sequencing analysis in biopsy from two HNSCC patients before and after cetuximab treatment.

2022-04-01 | GSE173647 | GEO

Overcoming cetuximab resistance in HNSCC: The role of AURKB and DUSP proteins

Project description:Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Out microarray results suggest that resistant cells still exhibit RAS-MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP 5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS-MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC 4 head and neck squamous cell carcinoma (HNSCC) cell lines were treated with either 15 nM cetuximab or PBS during 13 hours. For each cell line, differential gene expression was assessed between cetuximab and PBS treatments.

2014-09-18 | E-GEOD-61495 | biostudies-arrayexpress

Proteomics analysis of synergistic drug combination of midostaurin and BMS-754807 in Ewing sarcoma ASP14 cell line

Project description:We used quantitative mass spectrometry-based proteomics to unravel global changes in the phosphoproteome upon treatment of ASP14 cells (a Ewing Sarcoma cell line) according to the setup below. The combination of drugs were experimentally shown to infer synergy in terms of cell killing. Three experiments were performed using a triple SILAC setup (Light: Lys0,Arg0; Medium: Lys4,Arg6; and Heavy: Lys8,Arg10): Experiment 1: Light SILAC: Drug combination (90 nM Midostaurin + 20 nM BMS-754807) Medium SILAC: Midostaurin (90 nM) Heavy SILAC: 0.1% DMSO Experiment 2: Light SILAC: Drug combination (90 nM Midostaurin + 20 nM BMS-754807) Medium SILAC: Midostaurin (90 nM) Heavy SILAC: BMS-754807 (20 nM) Experiment 3: Light SILAC: Drug combination (90 nM Midostaurin + 20 nM BMS-754807) Medium SILAC: BMS-754807 (20 nM) Heavy SILAC: 0.1% DMSO ASP14 cells were starved by replacing complete SILAC medium with SILAC minimal medium without serum over night. Cells were treated with drugs as stated above for 2h; then they were stimulated with serum for 20 minutes and harvested thereafter.

2017-04-19 | PXD002765 | Pride

BMS-582664 in Combination With Erbitux in Patients With Advanced Gastrointestinal Malignancies

Project description:This is a phase I dose escalation study to determine the safety, pharmacokinetics and pharmacodynamics of BMS-582664 in combination with full dose erbitux in patients with advanced colorectal cancer who have received no more than 2 prior regimens for metastatic colorectal cancer.

| 2020028 | ecrin-mdr-crc

BMS-470539 on human synovial fibroblasts

Project description:Gene expression profile of BMS-470539 on human synovial fibroblasts.

2019-12-16 | GSE98658 | GEO

Safety and Efficacy Study of BMS-908662 Alone or in Combination With Cetuximab in Subjects With K-RAS or B-RAF Mutation Positive Advanced or Metastatic Colorectal Cancer

Project description:The purpose of the study is to identify a safe and tolerable dose of BMS-908662 in combination with cetuximab; and then to evaluate the tumor response to BMS-908662 when administered alone or in combination with cetuximab

| 2086270 | ecrin-mdr-crc

Methanosphaera sp. BMS

Project description:Methanosphaera sp. BMS Genome sequencing and assembly

| PRJNA310024 | ENA

Neoadjuvant BMS-813160, nivolumab, gemcitabine and nab-paclitaxel for pancreatic cancer

Project description:Background: Targeting tumor-associated macrophages through C-C chemokine receptor type 2 (CCRs) in pancreatic ductal adenocarcinoma (PDAC) improves the efficacy of chemotherapy and restores T cell immunity. Methods: We conducted a phase I/II single institution study (NCT03496662) combining chemotherapy gemcitabine and nab-paclitaxel (GnP), an oral CCR2/5 inhibitor BMS-813160 and nivolumab for four 28-day cycles as a neoadjuvant therapy for patients with borderline resectable (BR) or locally advanced (LA) PDAC. The recommended phase 2 dose (RP2D) of BMS-813160 was established in the standard 3+3 design. Primary end points were safety and objective response rate (ORR). Secondary end points included resection rate, progression-free survival (PFS) and overall survival (OS). Results: 8 patients were treated with GnP alone (control arm) and 31 patients (29 response evaluable) were treated at RP2D. No grade 3 or 4 toxicities attributed to nivolumab or BMS-813160 were identified. After all 4 cycles of study treatment (N=26), ORR was 35.7%, 16.7% among BR- and LA-PDAC patients, compared to 0% of control arm patients. 78.6% BR- and 16.7% of LA-PDAC patients who completed study treatment underwent surgical resection. For intent-to-treat analyses, BR-PDAC patients had a mPFS and mOS of 14.6 and 20.4 months respectively; and LA-PDAC patients had a mPFS and mOS of 14.7 and 17 months respectively. Single cell RNAseq analysis showed enhanced proliferating CD4 and CD8 T cells and gene signatures indicative of effector function. Conclusions: Neoadjuvant BMS-813160/nivolumab/GnP was well tolerated and appears to achieve higher ORR and resectability than historical data, warranting a larger randomized phase II study.

2025-03-11 | GSE288533 | GEO

Effect of BMS-582949 treatment on gene expression in osteoclasts

Project description:Controlling excessive osteoclastic activity is a promising strategy for many bone disease treatments. Here we report that 10 μM BMS-582949, a clinical p38α inhibitor,dromatically suppresses the osteoclast differentiation in vitro. Our results provide a evidence that BMS-582949 could be a candicdate drug for the therapy of osteolytic diseases.

2024-02-29 | GSE249860 | GEO

Discovery of BMS-986408, a First-In-Class Dual DGK⍺ and DGK Inhibitor That Unleashes PD-1 Checkpoint and CAR-T Cell Immunotherapies

Project description:DGKα and DGKζ are lipid kinases that negatively regulate T cell signaling through diacylglycerol (DAG) metabolism, making them attractive targets for next-generation immunotherapy. Here, we disclose the discovery and pre-clinical characterization of the first clinical-stage DGKα and DGKζ lipid kinase inhibitor, BMS-986408. BMS-986408 binds to the accessory subdomain of the catalytic domain and inhibits DGKα/ζ through a mechanism of action that includes DAG-substrate competitive inhibition, subcellular translocation to plasma membrane, and proteosome-dependent degradation. DGKα/ζ inhibition markedly improved the therapeutic benefit of PD-1 therapy by unleashing T cell responses in the tumor while also uniquely amplifying the priming and expansion of tumor-reactive T cells in the tumor-draining lymph nodes. Importantly, simultaneous inhibition of both DGKα and DGKζ was required to maximize combination benefit with PD-1 therapy. DGKα and DGKζ were broadly expressed in NSCLC tumor-infiltrated T cells and combination therapy invigorated a robust cytokine response in NSCLC patient-derived organotypic tumors supporting the clinical evaluation of this combination in NSCLC patients. BMS-986408 also markedly improved CD19-targeted CAR-T cell therapy efficacy by overcoming hypo-functionality, insufficient expansion, and lack of co-stimulatory ligands. BMS-986408 represents the first critical step towards evaluating the broad immunotherapy potential of DGKα/ζ inhibitors in cancer patients.

2025-04-04 | GSE293295 | GEO

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