Se tråden Biotekaksjer og en alternativ link av Boykie.
Fire treff på Bemcentinib:
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bull
Efficacy and Safety of Bemcentinib in Patients with Myelodysplastic Syndromes or Acute Myeloid Leukemia Failing Hypomethylating Agents
Results:
Between 2018 and 2020, 58 patients in 10 European centers were screened (MDS=27/AML=31) with a median age of 78 years (range, 62-86 years). 45 patients (MDS=21, AML=24) received at least one cycle of BEM and were eligible for safety and efficacy analysis after the first 4 months of treatment. Thirty six (80%) out of 45 patients were considered relapsed after a response to HMA, 8 (18%) had primary resistance and 1 patient (2%) had HMA intolerance. The median number of prior AZA or DAC cycles was 13. In addition, 18 patients (40%) (MDS=9/AML=9) were red blood cell transfusion-dependent.
Treatment with BEM was generally well tolerated with only low rates of grade 3-4 hematologic toxicities (n=7). Forty-seven serious adverse events (SAE) occurred in 22 patients (MDS=9/AML=13), mostly due to infectious complications (n=12), hematological toxicity (n=4) or gastrointestinal disturbance (n=6). Until the first 4 months of BEM treatment, the median number of BEM treatment cycles received was 1.5 (range, 0.5-4). During study, 9 patients (20%) died due to infection (MDS=1/AML=3), deterioration of general condition (MDS=1/AML=2) and progressive disease (MDS=0/AML=2). BEM treatment is currently ongoing in four patients (MDS=3/AML=1).
The primary endpoint was met in 9 of 45 patients (20.0%). Within the MDS cohort 33.3% achieved a response (n=7/21; CR=1, CRi= 3, SD=3), while 8.3% of patients (n=2/24) with AML achieved stable disease(SD). The 4 MDS patients achieving CR/CRi had a normal karyotype and a median baseline IPSS-R score of 4 (range 3-5). Among the MDS non-responders 4 patients had a complex karyotype, median IPSS-R score was 5 (range 3-5). Median baseline bone marrow blast count was 15% vs. 13% and median pretreatment hemoglobin-, platelet- and WBC levels were 9.2 g/dl (range 7.9-11.8 g/dl), 51 G/L(range 26-120 G/L) and 1.9x109/l (range 1.18-8.9 x109/l) vs. 9.6 g/dl (range 7.9-11.3 g/dl), 35 G/L (range 0-167 G/L) and 1.45x109/l (range 0.82-6.97 x109/l) comparing MDS responders (CR/CRi) vs MDS non-responders, respectively.
Preliminary data evaluating soluble AXL (sAXL) in blood plasma at baseline showed that 66.6 % (n=2/3) of MDS patients achieving CR/CRi displayed sAXL levels below a defined threshold, while this was only seen in 20% (n=2/10) of MDS non-responders.
Conclusion:
These results of the prospective phase II BERGAMO trial confirm, that single agent BEM is generally safe and well tolerated in this patient population with an unmet medical need. Importantly, BEM showed clinical efficacy in a subgroup of MDS patients. These encouraging clinical results are being further explored by an in depth translational research program aiming to identify additional molecular and biological prognostic factors associated with response
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Ble trangt inn døra på slutten her 
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Oral presentation her også! Sweet.
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Vil du dele tankene dine eller evt @Boykie vedr resultatet som foreligger her?
På forhånd takk
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BerGenBio presenterer oppdaterte kliniske data fra fase-II kombinasjonsstudien av bemcentinib og LDAC hos eldre pasienter med tilbakevennende AML på ASH 2020 konferansen
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Ser veldig bra ut dette for BergenBio! Dette må jo føre til kursøkning fremover. Et hav av triggere i vente!
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Fantastisk.Kan bli mye brukt for mange myelodysplastisketilstander, akutt myeloid leukemi,polycytemianvera etc.Kan muligens bli brukt som bremsemedisin før stamcelle? Det vi trenger et en AXL expression marker så kan dette bli standard behandling.
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Normal vitreous promotes angiogenesis via activation of Axl
First published: 05 November 2020
https://doi.org/10.1096/fj.201903105R
Vitreous has been reported to prevent tumor angiogenesis, but our previous findings indicate that vitreous activate the signaling pathway of phosphoinositide 3‐kinase (PI3K)/Akt, which plays a critical role in angiogenesis. The goal of this research is to determine which role of vitreous plays in angiogenesis‐related cellular responses in vitro. We found that in human retinal microvascular endothelial cells (HRECs) vitreous activates a number of receptor tyrosine kinases including Anexelekto (Axl), which plays an important role in angiogenesis. Subsequently, we discovered that depletion of Axl using CRISPR/Cas9 and an Axl‐specific inhibitor R428 suppress vitreous‐induced Akt activation and cell proliferation, migration, and tuber formation of HRECs. Therefore, this line of research not only demonstrate that vitreous promotes angiogenesis in vitro, but also reveal that Axl is one of receptor tyrosine kinases to mediate vitreous‐induced angiogenesis in vitro, thereby providing a molecular basis for removal of vitreous as cleanly as possible when vitrectomy is performed in treating patients with proliferative diabetic retinopathy.
(Diabetisk retinopati er en synsskade som følge av diabetes. Diabetes er en sykdom som ofte medfører komplikasjoner i øynene. Sykdommen er den hyppigste årsaken til blindhet blant mennesker i arbeidsfør alder i den industrialiserte del av verden. Skadene på synet skyldes hovedsakelig at det skjer endringer på øyets netthinne.)
Axl depletion suppressed vitreous‐stimulated Akt activation and angiogenesis in vitro (Figure [4]), suggesting that pharmacological inhibition of Axl could block vitreous‐induced Akt activation so that a potential pharmacological inhibitor could be used for treating retinal pathological angiogenesis. To this end, we found that 4 μM R428, a specific inhibitor of Axl, completely blocked vitreous‐induced Akt phosphorylation at S473 in HRECs, indicating that this drug at this concentration is able to abrogate vitreous‐stimulated Akt activation and cellular responses. As expected, R428 inhibited vitreous‐enhanced proliferation, migration, and tube formation of HRECs (Figure [5]), suggesting that Axl is a potential mediator of abnormal retinal angiogenesis.
Results showed a dramatic decrease in the number of preretinal tufts after treatment with R428 compared to vehicle (Figure [6A‐B]), and the tufts stand for pathological angiogenesis were outline in (Figure [6C‐D]). Taken together, these data show that inhibition of Axl prevents hypoxia‐induced pathological angiogenesis in a mouse model of OIR.
(Bemcentinib, also known as BGB324 or R428)
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Kunne nesten tro Bemcentinib er ‘snake oil’ og kan brukes til det meste. Men det virker ha dokumentert effekt på flere områder.
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BERGENBIO HOSTING VIRTUAL R&D DAY TODAY
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R&D dagen i sin helhet: https://vimeo.com/477021607
Veldig bra gjennomgang og veldig lærerikt kring AML, MDS (første 39 minuttene), Lung cancer (fra 39 min), hvorfor Bemcentinb burde testes i Mesothelioma sammen med Nivolumab/ipilimumab. (fra 51 min), SARS-CoV-2 (fra 1:08) og Fibrosis(Fra 1:38). Clinical development plan starter på 2:08.
Vel verdt tiden og veldig informativt kring indikasjonene og ikke bara BGBIO spesifikt.
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Flott, takk for den. Gikk glipp av fibrose-delen av konferansen.
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AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations
Received: 30 September 2020 / Accepted: 6 November 2020 / Published: 10 November 2020
https://www.mdpi.com/1422-0067/21/22/8419/htm (DOI)
In this review, we summarize the current knowledge of AXL functions and its implications in breast cancer progression.
Litt repetisjon på en tirsdag er vel sunt.
AXL Selective Inhibitors
BGB324 (Bemcentinib or R428) is the more selective ATP-competitive inhibitor of AXL (IC50 = 14 nM) and was the first to enter clinical trials to treat several cancer forms, such as TNBC tumors, metastatic melanoma and NSCLC. By blocking AXL autophosphorylation on tyrosine residue Y821, in vitro, it induces apoptosis, inhibits cancer cell invasion and reverts erlotinib resistance in TNBC cells; in vivo, BGB324 reduces cancer metastasis. In a recent preclinical study, BGB324 was tested in combination with auranofin, a gold phosphine derivative, initially used for the treatment of rheumatoid arthritis and also studied for the treatment of the other diseases, such as breast cancer. It is a thioredoxin reductase inhibitor and appears to induce apoptosis through PI3K pathway inhibition. The authors of this study have observed that in different breast cancer settings (MDA-MB231 and MCF7), the combination of BGB234 and auranofin reduced cell growth by inducing apoptosis, mediated by increased levels of Bcl-2-associated X-protein (BAX). Recently, BGB324 was implicated in a phase II clinical trial (NCT03184558) for TNBC and inflammatory breast cancers, in combination with pembrolizumab; however, the results have not yet been released
To date, BGB324 is the only AXL-specific inhibitor to be involved in clinical trials, although other highly selective molecules have been developed. Of these, however, there are only promising preclinical data which need to be extensively investigated. It is, therefore, clear that the process of development and the testing of new selective AXL inhibitors will require more time and more extensive studies, in the clinical field also. Analyzing the results described in this review, it is clear that AXL can be a potential marker in which to invest for breast cancer management and not only this, but there is still no solid and definitive evidence on its role in the clinical field. For this reason, it is auspicious to increase the study of selective inhibitors for AXL that can also be combined with other therapeutic regimens.
In recent years, cancer treatments have made important progress and the discovery of new target therapies has greatly improved the lives of patients and survival rates. However, despite the promising results obtained, oncology research has not solved two problems that are the causes of the most cancer deaths: (1) metastasis, with new characteristics as compared to the primary tumor; (2) drug resistance. For these reasons, it is essential to identify and study, always, new and alternative molecular targets to bypass these unfortunate conditions. Given its highly oncogenic characteristics and its involvement in many pro-tumorigenic processes, currently, AXL is considered a valid biomarker in several tumor contexts, primarily breast cancer. In this pathology, through uncontrolled activation of different downstream effectors, such as PI3K and MAPK, AXL regulates the malignant progression and migratory properties of breast cancer cells. Especially in TNBC tumors, AXL has been considered a key factor in the EMT process, promoting a mesenchymal and invasive phenotype. No less important is the role of AXL in several mechanisms of pharmacological resistance involved in the disease’s relapse, even in contexts previously responding to treatments. To date, several agents which inhibit the GAS6/AXL axis are being studied and have led to important results from both in vitro and in vivo experiments. Certainly, BGB324, due to its high selectivity for AXL, is the drug that has mainly produced significant results in terms of growth inhibition; in addition, it is the only specific AXL inhibitor to be involved in clinical trials for the treatment of several cancers. The development of new anti-AXL agents is always active, but even if preclinical studies have produced encouraging results in multiple tumor contexts, there is still a long way to go in clinical trials. Indeed, although different inhibitors of AXL have been developed, many of these are multi-target and are often implicated in clinical trials not for their inhibitory role on AXL. Therefore, the construction of new drugs, increasingly selective for this receptor, is always expected.
(Bemcentinib, also known as BGB324 or R428)
Edit:
La til «AXL Selective Inhibitors».
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BerGenBio presenterer fase-II bemcentinib kombinasjonsstudie i ikke-småcellet lungekreft (NSCLC) på den årlige SITC konferansen
BERGENBIO PRESENTS PHASE II BEMCENTINIB COMBINATION STUDY IN NSCLC AT ANNUAL SITC MEETING
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Var det noe særlig nytt her da? Dette er vel mer eller mindre det samme meldt i sommer…?
Var vel cohort A som ble meldt i sommer.