BMS-833923 / BMS, Exelixis - LARVOL DELTA

TARGETING THE HEDGEHOG PATHWAY TRANSCRIPTION EFFECTOR Gli2 IS A NOVEL THERAPEUTIC STRATEGY FOR SEVERE SCHISTOSOMIASIS MANSONI FIBROSIS AND PORTAL HYPERTENSION (AASLD 2023) - " Hh/IL13 signaling were investigated by qRT-PCR, immunohistochemistry and ELISA in uninfected healthy transplant donors (n=22), infected hepatointestinal schistosomiasis patients (liver granulomas, low fibrosis, n=17), infected hepatosplenic patients (advanced fibrosis and portal hypertension n=72); in Schistosoma mansoni infected mice (wild-type, IL13Rα1-/- and TKO (IL-10-/- IL12p40-/-IL13Rα2-/-) treated with anti-IL13 antibody, Hh pathway inhibitors (Smoothened antagonists Vismodegib or XL139 vs Gli2 antagonists Arsenic Trioxide (ATO) or HPI vs Vehicle), in mice overexpressing IL13 (plasmid) and in human liver cells stimulated with recombinant IL13 (rIL13) and treated with STAT6 siRNA, Vismodegib or HPI). Activation of the Hh pathway in schistosomiasis is highly dependent on IL13-mediated signaling. Targeting Hh pathway with Gli2 antagonists may be a novel therapeutic strategy to treat schistosomiasis fibrosis and portal hypertension."

Cardiovascular • Fibrosis • Hepatology • Hypertension • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Portal Hypertension • Transplantation • GLI1 • GLI2 • GLI3 • IL10 • IL13 • IL13RA2 • STAT6

Repurposing the Hedgehog pathway inhibitor, BMS-833923, as a phosphatidylglycerol-selective membrane-disruptive colistin adjuvant against ESKAPE pathogens. (PubMed, Int J Antimicrob Agents) - "Mechanistic studies revealed that BMS caused membrane disruption by targeting membrane phospholipid phosphatidylglycerol (PG) and cardiolipin (CL), promoting membrane dysfunction, metabolic disturbance, leakage of cellular components, and ultimately cell death. The current study describes a potential strategy to enhance colistin efficacy and combat multidrug-resistant ESKAPE pathogens."

Journal • Infectious Disease • Metabolic Disorders

New Ameloblastoma Cell Lines Enable Preclinical Study of Targeted Therapies. (PubMed, J Dent Res) - "AB cells with activating SMO-L412F mutation (Hedgehog pathway) are insensitive to vismodegib; however, a distinct small-molecule SMO inhibitor, BMS-833923, significantly reduces both downstream Hedgehog signaling and tumor cell viability. The novel cell line resource enables preclinical studies and promises to speed the translation of new molecularly targeted therapies for the management of ameloblastoma and related odontogenic neoplasms."

Journal • Preclinical • CNS Disorders • Oncology • Psychiatry • BRAF • FGFR2 • KRAS • NRAS • PIK3CA • SMO

Sonic hedgehog is Essential for Proximal-Distal Outgrowth of the Limb Bud in Salamanders. (PubMed, Front Cell Dev Biol) - "In rescuing limb development by implanting SHH-N protein beads into the nascent limb field of Shh crispants, we show that the limb field is specified in the absence of Shh and that hedgehog pathway activation is required to initiate proximodistal outgrowth. When our results are examined alongside other derived aspects of salamander limb development and placed in a phylogenetic context, a new hypothesis emerges whereby the ability for cells at an amputation plane to activate morphogenesis and regenerate a limb may have evolved uniquely in urodeles."

Journal

Basal epidermis collective migration and local sonic hedgehog signaling promote skeletal branching morphogenesis in zebrafish fins. (PubMed, Dev Biol) - "The Smo inhibitor BMS-833923 prevents branching in all fins, paired and unpaired, with surprisingly minimal effects on caudal fin initial skeletal patterning, ray outgrowth or bone differentiation...We use live cell tracking to find Shh/Smo restrains the distal movement of basal epidermal cells by apparent 'tethering' to pre-osteoblasts. We propose short-range Shh/Smo signaling promotes these heterotypic associations to couple instructive basal epidermal collective movements to pre-osteoblast repositioning as a unique mode of branching morphogenesis."

Journal • SMO

A Study of BMS-833923 With Carboplatin and Etoposide Followed by BMS-833923 Alone in Subjects With Extensive-Stage Small Cell Lung Cancer (clinicaltrials.gov) - P1; N=5; Completed; Sponsor: Bristol-Myers Squibb; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • GLI1

A Study of BMS-833923 With Carboplatin and Etoposide Followed by BMS-833923 Alone in Subjects With Extensive-Stage Small Cell Lung Cancer (clinicaltrials.gov) - P1; N=5; Completed; Sponsor: Bristol-Myers Squibb; N=36 ➔ 5

Clinical • Combination therapy • Enrollment change • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • GLI1

Multiple ascending dose (MAD) combination in subjects with multiple myeloma (clinicaltrials.gov) - P1, N=66 -> 27; Recruiting -> Completed; Completion date: Jun 2013 -> Mar 2012

Enrollment change • Trial completion • Trial completion date • Multiple Myeloma

Simultaneous Inhibition of MEK and Hh Signaling Reduces Pancreatic Cancer Metastasis. (PubMed, Cancers (Basel)) - "By combining Hh signaling inhibitor BMS833923 with RAS downstream MEK signaling inhibitor AZD6244, we observed reduced number of metastatic nodules in several mouse models for pancreatic cancer metastasis. In vitro, Ly6G⁺ CD11b⁺ cells can stimulate cancer cell proliferation, and this effect is sensitive to MEK and Hh inhibition. Our studies may help design novel therapeutic strategies to mitigate pancreatic cancer metastasis."

IO Biomarker • Journal • Biosimilar • Gastrointestinal Cancer • Genito-urinary Cancer • Immune Modulation • Inflammation • Lung Cancer • Oncology • Pancreatic Cancer • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Thoracic Cancer

Phase 2 Dasatinib Combo With Smoothened (SMO) Antagonist (BMS-833923) (clinicaltrials.gov) - P2; N=66; Completed; Sponsor: Bristol-Myers Squibb; Active, not recruiting ➔ Completed

Trial completion • Biosimilar • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

Hedgehog signaling-mediated adaptation to hypoxic microenvironment promotes osteoclastogenesis in advanced breast cancer (SABCS 2019) - "Hence, we inhibited Hh signaling using small molecule inhibitor GANT61 (GLI inhibitor) and pharmacological inhibitor BMS833923 (SMO inhibitor).Since hypoxic microenvironment is prevalent in the bone, we investigated the effect of conditioned medium from breast cancer cells in hypoxic condition on bone marrow-derived macrophages (BMDMs)...In the future, we will further investigate the mechanistic role of Hh signaling-mediated modulation of HIF-1α. This study will possibly yield new therapeutic targets in controlling hypoxia-mediated cancer metabolism and tumorigenesis of breast cancer.This work is supported by NIH grant R01CA169202"

Osteopontin

Hedgehog Signaling Inhibition by Smoothened Antagonist BMS-833923 Reduces Osteoblast Differentiation and Ectopic Bone Formation of Human Skeletal (Mesenchymal) Stem Cells. (PubMed, Stem Cells Int) - "Further bioinformatic analysis employing Ingenuity Pathway Analysis revealed significant enrichment in BMS-833923-treated cells for a number of functional categories and networks involved in connective and skeletal tissue development and disorders, e.g., NFκB and STAT signaling. We identified SMO/Hedgehog antagonist (BMS-833923) as a powerful inhibitor of osteoblastic differentiation of hMSC that may be useful as a therapeutic option for treating conditions associated with high heterotopic bone formation and mineralization."

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