Bemencentinib er en selektiv AXL-hemmer fra BerGenBio, et norsk biotek-selskap på Oslo børs. Medisinen testes i flere kliniske fase 2-studier, og har blant annet vist lovende effekt mot mange kreftformer og virus.
Dette er ment å være en ressursside som samler lenker til eksterne medisinske artikler og informasjon om bemcentinib, også kalt BGB324 og R428, samt relevante artikler om AXL, sortert etter dato med nyeste først. For en liste over presentasjoner og studier utført av BerGenBio, se listen på deres egen hjemmeside under avsnittet «Scientific Presentations».
Jeg har også laget en egen ressursside kun for bemcentinib mot covid-19, den finner du her: Bemcentinib fra BerGenBio mot covid-19.
AACR: Association of AXL and PD-L1 expression with clinical outcomes in patients with advanced renal cell carcinoma treated with PD-1 blockade: «Our findings propose AXL as candidate factor of resistance to PD-1 blockade, and provide compelling support for screening both AXL and PD-L1 expression in the management of advanced ccRCC.»
RareDiseaseAdvisor: Targeting a Subpopulation of GIST Cells Could Overcome Post-Treatment Disease Persistence: «They found that tumors with low KIT expression overexpressed cancer stem cell gene signatures, a finding in accordance with the results of the in vitro experiments. Tumors with low KIT expression also had activation of the Gas6/AXL pathway and NF-κB signaling gene signatures. The researchers decided to treat these tumors with an AXL inhibitor (bemcentinib) and an NF-κB inhibitor (bardoxolone), either on their own or in combination with imatinib. They found that both agents alone or in combination with imatinib effectively targeted primary imatinib-resistant GIST cells.»
Europe PMC: AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms: «Bemcentinib reduces tumor growth in vivo», «Bemcentinib prolongs survival and reduces spleen size in MPN in vivo», «In summary, our data highlight AXL inhibition as a new therapeutic approach in MPN and support the need for clinical trials of bemcentinib.»
Dovepress: Targeting AXL in NSCLC: «Yang et al evaluated the therapeutic potential of the AXL/MET selective inhibitors, BGB324 and cabozantinib, in cell and mouse xenograft models of lung squamous cell carcinoma (SCC). In preclinical settings, these AXL targeting compounds alone were significantly efficacious. AXL has also been reported as an oncogene in thyroid cancers, pancreatic ductal carcinoma (PDAC), gastric cancer, metastatic prostate cancer and melanoma.»
Wiley: Axl-inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model. «In conclusion, our data indicate that mitochondria and mitochondrial-related pathways are dramatically affected by UUO surgery. Bemcentinib partially reverses the effects of UUO, without affecting non-ligated kidneys or SHAM-operated mice, and thereby qualifies as a promising treatment in kidney disease.»
AACR: Abstract 1210: NFX1-123: A potential therapeutic target in cancer. «The top four compounds were used to treat HPV- and HPV+ cervical and head and neck cancer cell lines in culture, and two (R428 and Ketoconazole) were found to reduce NFX1-123 protein levels and inhibit cell growth and survival. R428 was also found to inhibit NFX1-123 and regulate autophagy and autophagy-mediated cell death. Conclusion: Nine out of 25 (36%) cancers expressed high levels of NFX1-123, and drug targeting of NFX1-123 can lead to cell growth inhibition. NFX1-123 may be a potential novel therapeutic target in cancers that highly express NFX1-123.»
AACR: Abstract 3154: Host and neoplastic cell Axl inhibition impair prostate and breast cancer bone metastasis. «The goal of the present study was to characterize the role of Axl signaling in prostate and breast cancer cell dissemination to bone. This was accomplished using Axl knockdown neoplastic cells, a selective small molecule Axl inhibitor (BGB324), and osteoclast progenitor cells in vitro, as well as intracardiac injection of Axl knockdown tumor cells in vivo. The results showed that Axl inhibition significantly decreases tumor cell migration and invasion in vitro, and suppression of Axl signaling in osteoclast precursor cells reduces the formation of mature osteoclasts. In vivo, Axl knockdown in prostate and breast cancer cells significantly suppressed the formation of neoplastic bone lesions. Taken together our findings indicate that therapeutic targeting of Axl may impair tumor metastasis to the bones through neoplastic and host cell signaling axes.»
AACR: AXL inhibition in macrophages stimulates host-versus-leukemia immunity and eradicates naive and treatment resistant leukemia: «Remarkably, AXL deficiency in macrophages also enables PD1 checkpoint blockade in PD1-refractory leukemias. Lastly, we provide proof-of-concept that a clinical grade AXL inhibitor can be used in combination with standard of care therapy to cure established leukemia, regardless on AXL expression in malignant cells.»
Frontiers: AXL overexpression in tumor-derived endothelial cells promotes vessel metastasis in patients with hepatocellular carcinoma. «R428, an inhibitor of AXL, significantly abolished the increased tumor volume, liver metastasis, and vessel metastasis in the xenograft nude mice inoculated subcutaneously with HCC-LM3 cells plus HUVEC-AXL-OE or HUVEC-AXL-NC cells. Similarly, in the PDX model, R428 significantly reduced the tumor volume and CD31 protein expression in HCC tumor tissues.»
NCBI: Perivascular cell-derived extracellular vesicles stimulate colorectal cancer revascularization after withdrawal of antiangiogenic drugs. «Collectively, these results suggest that R428 blocks tumour perivascular cell EV-Gas6-mediated activation of the Axl signalling pathway in EPCs, enhances the therapeutic efficacy of regorafenib, and increases the survival time of mice with metastatic colorectal cancer.»
MDPI: Resistance to Immune Checkpoint Blockade in Uterine Leiomyosarcoma: What Can We Learn from Other Cancer Types? «Evidence suggests that dysregulated tumor-intrinsic pathways, such as the PI3K/mTOR, Wnt/ß-catenin, and AXL signaling pathways, might play a key role in ICB resistance by endorsing the expression of an immunosuppressive cytokine profile and facilitating the trafficking of immunosuppressive cell populations to the TME of uLMS.»
Frontiers: Radiosensitization in Pediatric High-Grade Glioma: Targets, Resistance and Developments. «Notably, while panobinostat was observed to function as a radiosensitizer alone, it could not prevent tumor regrowth. However, the addition of BGB324, having no significant radiosensitizing effect on its own, produced robust triple synergy in combination with panobinostat and RT and completely abolished tumor growth.»
SpringerLink: Inhibition of the Axl pathway impairs breast and prostate cancer metastasis to the bones and bone remodeling. «Our studies showed that pharmacologic Axl inhibition by BGB324 impaired tumor cell migration and invasion. In addition to its effects on tumor cells, we demonstrated that BGB324 impaired RANK-L-induced osteoclast maturation and differentiation in osteoclast precursor cells and BMDCs derived from female BALB/c mice. Taken together, we predict that pharmacologic inhibition of Axl will target neoplastic as well as stromal cells in the tumor microenvironment and hence impair tumor progression and metastasis.»
MDPI: Growth Arrest-Specific Factor 6 (GAS6) Is Increased in COVID-19 Patients and Predicts Clinical Outcome. «Specific AXL inhibition with bemcentinib was enough to diminish cytokine expression upon LPS exposure, particularly decreasing MCP-1 levels significantly. Interestingly, MCP-1 has also been proposed as a biomarker associated with disease severity of COVID-19, suggesting that MCP-1 reduction obtained after AXL inhibition may be involved in less recruitment of monocytes and thrombosis protection.»
MDPI: The Role of the Receptor Tyrosine Kinase Axl in Carcinogenesis and Development of Therapeutic Resistance: An Overview of Molecular Mechanisms and Future Applications. «Oxidative stress can activate Axl phosphorylation. The activation of Axl by H2O2, a reactive oxygen species (ROS) may be mediated partly via an increased intrinsic tyrosine kinase activity of Axl or decreased tyrosine phosphatase activity. In mesothelioma cells, ROS induced Axl phosphorylation which was consequently inhibited by BGB324 a selective inhibitor of Axl.»
NCBI: Novel AXL-targeted agents overcome FLT3 inhibitor resistance in FLT3-ITD+ acute myeloid leukemia cells. «In conclusion, upregulation of AXL antigen expression was associated with FLT3-ITD/TKD+ AML, particularly drug-resistant FLT3-ITD+ AML. Therefore, targeting AXL has clinical value in FLT3-mutant AML. The AXL-targeted agents DAXL-88, DAXL-88-MMAE and R428 could effectively inhibit the growth of FLT3-mutant AML cells and FLT3-ITD+ AML blast cells, and overcome resistance in the AC220-resistant MV4-11/AC220 cell line and FLT3 inhibitor-resistant AML blast cells.»
PubMed: Targeting the AXL Receptor in Combating Smoking-Related Pulmonary Fibrosis. «Pharmacological inhibition of AXL with AXL-specific inhibitor R428 showed selectivity for smoke-exposed fibroblasts. In all, our data suggest that AXL is a potential marker for smoke-associated PF and that targeting of the AXL pathway is a potential therapeutic strategy in treating tobacco-smoking related PF.» (bak betalingsmur)
MDPI: TAM Receptor Inhibition–Implications for Cancer and the Immune System. «The strong oncogenic properties of Axl expression and signaling have led to the development of Axl inhibitors; one of the best known to date is bemcentinib (formerly BGB324 or R428). It has been shown to block proliferation and growth signaling as well as tumor metastasis. Furthermore, Axl inhibition enhances apoptosis mediated by chemotherapeutic drugs. Due to the success of Axl inhibitors in preclinical models, some treatment prospects have been advanced into clinical testing. The lead candidate is bemcentinib, being tested in as much as ten clinical phase I/II studies registered on ClinicalTrials.gov.»
AACR: AXL Inhibition Induces DNA Damage and Replication Stress in Non–Small Cell Lung Cancer Cells and Promotes Sensitivity to ATR Inhibitors. «Here, we show that BGB324 (bemcentinib), a selective small-molecule AXL inhibitor, caused DNA damage and induced replication stress, indicated by ATR/CHK1 phosphorylation, more significantly in TP53-deficient NSCLC cell lines. Similar effects were also observed in large-cell neuroendocrine carcinoma (LCNEC) cell lines.» (bak betalingsmur)
CancerNetwork: Phase 2 Study Finds Bemcentinib Plus Pembrolizumab Well-Tolerated, Clinically Active in Advanced NSCLC. «This ongoing study supports the continued development of AXL inhibition with bemcentinib in order to extend the efficacy of immunotherapy in biomarker-selected refractory non—small cell lung cancer, according to Matthew G. Krebs, MB ChB, FRCP, PhD.»
JCI: Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization. «BGB324 specifically inhibits the catalytic and procancerous activities of Axl, but does not affect the binding between Gas6 and Axl. The results of Axl activity inhibition by BGB324 treatment concurred with the findings of anti-Axl mAb treatment. The inhibition of Axl restored the protective immunity to pneumococcal infection. Thus, the Gas6/Axl axis is a promising drug target for reducing the bacterial burden upon secondary bacterial infection.»