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DRUG:

volasertib (NBL-001)

i
Other names: NBL-001, BI6727, BI-6727, BI 6727, NBL001, NBL 001
Company:
Boehringer Ingelheim, Notable Labs, Oncoheroes
Drug class:
PLK1 inhibitor
14d
Single-cell landscape of innate and acquired drug resistance in acute myeloid leukemia. (PubMed, Nat Commun)
Unsupervised data integration reveals reduced ex vivo response to the Bcl-2 inhibitor venetoclax (VEN) in patients treated with both a hypomethylating agent (HMA) and VEN, compared to those pre-exposed to chemotherapy or HMA alone. Integrative analysis identifies both known and unreported mechanisms of innate and treatment-related VEN resistance and suggests alternative treatments, like targeting increased proliferation with the PLK inhibitor volasertib. Additionally, high CD36 expression in VEN-resistant blasts associates with sensitivity to CD36-targeted antibody treatment ex vivo. This study demonstrates how single-cell multi-omic profiling can uncover drug resistance mechanisms and treatment vulnerabilities, providing a valuable resource for future AML research.
Journal • IO biomarker
|
CD36 (thrombospondin receptor)
|
Venclexta (venetoclax) • volasertib (NBL-001)
20d
Polo-like Kinase 1 Predicts Lymph Node Metastasis in Middle Eastern Colorectal Cancer Patients; Its Inhibition Reverses 5-Fu Resistance in Colorectal Cancer Cells. (PubMed, Cells)
To investigate PLK1's role in chemoresistance, we used the specific inhibitor volasertib, which effectively reversed 5-Fu resistance...Furthermore, the knockdown of Zeb1 attenuated EMT and stemness, suggesting a possible link between EMT activation and the maintenance of stemness in CRC. Our findings underscore the pivotal role of PLK1 in mediating chemoresistance and suggest that PLK1 inhibition may represent a potential therapeutic strategy for the management of aggressive colorectal cancer subtypes.
Journal
|
PLK1 (Polo Like Kinase 1) • ZEB1 (Zinc Finger E-box Binding Homeobox 1)
|
ZEB1 expression
|
volasertib (NBL-001)
1m
NOD2 reduces the chemoresistance of melanoma by inhibiting the TYMS/PLK1 signaling axis. (PubMed, Cell Death Dis)
NOD2 inhibits thymidylate synthase (TYMS) expression by promoting K48-type ubiquitination modification of TYMS, thereby decreasing the resistance of melanoma cells to 5-fluorouracil (5-FU) and capecitabine (CAP). Furthermore, we revealed that the combination of the PLK1 inhibitor volasertib (BI6727) with 5-FU or CAP had a synergistic effect repressing the proliferation, migration, and autophagy of melanoma cells. Overall, our research highlights the protective role of NOD2 in melanoma and suggests that targeting NOD2 and the TYMS/PLK1 signaling axis is a high-profile therapy that could be a prospect for melanoma treatment.
Journal
|
TYMS (Thymidylate Synthetase) • PLK1 (Polo Like Kinase 1) • NLRC5 (NLR Family CARD Domain Containing 5)
|
TYMS expression
|
5-fluorouracil • capecitabine • volasertib (NBL-001)
5ms
MYC and HSF1 Cooperate to Drive PLK1 inhibitor Sensitivity in High Grade Serous Ovarian Cancer. (PubMed, bioRxiv)
Targeting PLK1 with the compound volasertib (BI-6727) revealed a greater than 200-fold increased potency of volasertib in HSF1-MYC co-amplified ovarian cancer cells compared to ovarian cancer cells wild-type HSF1 and MYC copy number, which extended to several growth assays, including spheroid growth. Volasertib, and other PLK1 inhibitors, have not shown great success in clinical trials and this study suggests that targeting PLK1 may be viable in a precision medicine approach using HSF1-MYC co-amplification as a biomarker for response.
Journal
|
HSF1 (Heat Shock Transcription Factor 1)
|
volasertib (NBL-001)
5ms
Resistance to Spindle Inhibitors in Glioblastoma Depends on STAT3 and Therapy Induced Senescence. (PubMed, bioRxiv)
Treating glioblastomas with the spindle inhibitors ispinesib, alisertib, or volasertib creates a subpopulation of therapy induced senescent cells that resist these drugs by relying upon the anti-apoptotic and metabolic effects of activated STAT3. These results support a therapeutic strategy of targeting STAT3-dependent therapy-induced senescence to enhance the efficacy of spindle inhibitors for the treatment of glioblastoma. • Resistance to non-microtubule spindle inhibitors limits their efficacy in glioblastoma and depends on STAT3.• Resistance goes hand in hand with development of therapy induced senescence (TIS).• Spindle inhibitor resistant glioblastomas consist of three cell subpopulations-proliferative, quiescent, and TIS-with proliferative cells sensitive and quiescent and TIS cells resistant.• TIS cells secrete TGFβ, which induces proliferative cells to become quiescent, thereby expanding the population of resistant cells in a spindle inhibitor resistant glioblastoma• Treatment with a STAT3 inhibitor kills TIS cells and restores sensitivity to spindle inhibitors.
Journal
|
STAT3 (Signal Transducer And Activator Of Transcription 3) • TGFB1 (Transforming Growth Factor Beta 1)
|
volasertib (NBL-001) • alisertib (MLN8237) • ispinesib (SB-715992)
6ms
PLK1 inhibition leads to mitotic arrest and triggers apoptosis in cholangiocarcinoma cells. (PubMed, Oncol Lett)
Different CCA cell lines developed from Thai patients, HuCCA1, KKU055, KKU100 and KKU213A, were treated with two PLK1 inhibitors, BI2536 and BI6727, and were transfected with small interfering RNA, followed by analysis of cell proliferation, cell cycle distribution and cell apoptosis. Validation of the antiproliferative effects of PLK1 inhibition was accomplished through silencing of the PLK1 gene. In conclusion, targeting PLK1 provided promising results for further study as a potential candidate for targeted therapy in CCA.
Journal
|
AURKA (Aurora kinase A) • CCNB1 (Cyclin B1)
|
volasertib (NBL-001) • BI2536
8ms
Targeting Oral Squamous Cell Carcinoma with Combined Polo-Like-Kinase-1 Inhibitors and γ-Radiation Therapy. (PubMed, Biomedicines)
The combinatorial efficacy of volasertib and radiotherapy was replicated in xenograft mouse models. These findings highlight the potential of adding PLK-1 inhibitors to adjuvant therapy regimens in OSCC.
Journal
|
PLK1 (Polo Like Kinase 1)
|
volasertib (NBL-001)
9ms
PLK1 and FoxM1 expressions positively correlate in papillary thyroid carcinoma and their combined inhibition results in synergistic anti-tumor effects. (PubMed, Mol Oncol)
The combined treatment of a PLK1 inhibitor (volasertib) and a FoxM1 inhibitor (thiostrepton) demonstrated a synergistic effect in reducing PTC cell growth in vitro and delaying tumor growth in vivo. This study highlights the important role of PLK1 in PTC tumorigenesis and prognosis. It also highlights the synergistic therapeutic potential of dual-targeting PLK1 and FoxM1 in PTC, unveiling a potential innovative therapeutic strategy for managing aggressive forms of PTC.
Journal
|
PLK1 (Polo Like Kinase 1) • FOXM1 (Forkhead Box M1)
|
volasertib (NBL-001) • thiostrepton (RSO-021)
9ms
Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM). (PubMed, Blood Cancer J)
GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.
Journal • IO biomarker
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • RUNX1 (RUNX Family Transcription Factor 1) • MCL1 (Myeloid cell leukemia 1) • CDK6 (Cyclin-dependent kinase 6) • MECOM (MDS1 And EVI1 Complex Locus)
|
RUNX1 mutation • BCL2 expression • MYC expression
|
volasertib (NBL-001) • Synribo (omacetaxine mepesuccinate) • mebendazole
10ms
PLK1 and PARP positively correlate in Middle Eastern breast cancer and their combined inhibition overcomes PARP inhibitor resistance in triple negative breast cancer. (PubMed, Front Oncol)
In vitro studies were conducted using the PLK1 inhibitor volasertib and the PARP inhibitor olaparib, either alone or in combination, in PTC cell lines. Moreover, our findings indicate that inhibition of PLK1 can reinstate sensitivity in PARP inhibitor (PARPi) resistant TNBC cell lines. Our results shed light on the role of PLK1 in the pathogenesis and prognosis of Middle Eastern BC and support the potential clinical development of combined inhibition of PLK1 and PARP, a strategy that could potentially broaden the use of PLK1 and PARP inhibitors beyond BC cases lacking BRCA.
Journal • BRCA Biomarker • PARP Biomarker
|
BRCA (Breast cancer early onset) • PLK1 (Polo Like Kinase 1)
|
PLK1 overexpression • BRCA mutation
|
Lynparza (olaparib) • volasertib (NBL-001)
11ms
Diosgenin potentiates the anticancer effect of doxorubicin and volasertib via regulating polo-like kinase 1 and triggering apoptosis in hepatocellular carcinoma cells. (PubMed, Naunyn Schmiedebergs Arch Pharmacol)
DG showed promising chemo-modulatory effects to Vola and DOX against HCC that may be attributed partly to the downregulation of PLK1 and PCNA, upregulation of tumor suppressor protein P53, and apoptosis induction. Thus, DG combination with chemotherapy may be a promising treatment approach for HCC.
Journal • PARP Biomarker
|
PARP1 (Poly(ADP-Ribose) Polymerase 1) • PLK1 (Polo Like Kinase 1) • CASP3 (Caspase 3) • PCNA (Proliferating cell nuclear antigen)
|
TP53 expression • PCNA expression
|
doxorubicin hydrochloride • volasertib (NBL-001)
12ms
A Phase 2 Study with Volasertib for Ven-HMA Relapsed/Refractory Acute Myeloid Leukemia Patients Guided By a Predictive Precision Medicine Platform (ASH 2023)
A BI Phase 2 study showed volasertib combined with low-dose cytarabine (V+LDAC) delivered a complete response (CR) + CR with incomplete count recovery (CRi) rate of 31. Secondary endpoints include an assessment of the diagnostic performance characteristic of Notable's drug sensitivity score in predicting in vivo volasertib clinical response. Specific strategies, including tailored dosing, robust infection control, and carefully selecting drug combination partners are designed to mitigate the adverse events observed in BI's Phase 3 trial and maximize volasertib's therapeutic impact regarding both efficacy and safety.
Clinical • P2 data
|
PLK1 (Polo Like Kinase 1)
|
cytarabine • volasertib (NBL-001)
12ms
Combined Inhibition of UBE2C and PLK1 Reduce Cell Proliferation and Arrest Cell Cycle by Affecting ACLY in Pan-Cancer. (PubMed, Int J Mol Sci)
By combining the PLK1 inhibitor volasertib and the ACLY inhibitor bempedoic acid, it showed a higher synergistic inhibition of cell viability and higher synergy scores in seven cell lines, compared with those of other combination treatments. Our study reveals the potential mechanisms through which cell-cycle-related genes regulate metabolism and proposes a potential combined targeted therapy for patients with higher PLK1 and ACLY expression in pan-cancer.
Journal • Pan tumor
|
IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • BIRC5 (Baculoviral IAP repeat containing 5) • PLK1 (Polo Like Kinase 1) • ACLY (ATP Citrate Lyase) • UBE2C (Ubiquitin Conjugating Enzyme E2 C)
|
BIRC5 expression
|
volasertib (NBL-001)
1year
Specific Polo-like kinase 1 (PLK1) expression in Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) suggests an intact immune surveillance program. (PubMed, Am J Pathol)
Overall, the findings demonstrate that PLK1 signaling increases NLPHL proliferation and constitutes a potential vulnerability that can be targeted with PLK1 inhibitors. In addition, the findings suggest that an active immune surveillance program in NLPHL may be a critical mechanism limiting PLK1-dependent tumor growth.
Journal
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • PLK1 (Polo Like Kinase 1)
|
volasertib (NBL-001)
1year
The effect of PLK1 inhibitor in osimertinib resistant non-small cell lung carcinoma cells. (PubMed, Zhejiang Da Xue Xue Bao Yi Xue Ban)
PLK1 inhibitors have a synergistic effect with osimertinib on osimertinib-resistant NSCLC cells which indicates that they may have potential clinical value in the treatment of NSCLC patients with osimertinib resistance.
Journal
|
EGFR (Epidermal growth factor receptor)
|
EGFR mutation • EGFR H1975
|
Tagrisso (osimertinib) • volasertib (NBL-001) • BI2536 • GSK461364
1year
The effect of PLK1 inhibitor in Osimertinib resistant NCI-H1975 cell lines. (PubMed, Zhejiang Da Xue Xue Bao Yi Xue Ban)
PLK1 inhibitors combined with Osimertinib behave stronger anti-tumor effect to Osimertinib-resistant NSCLC cells and may be used for intervention and treatment of Osimertinib resistance.
Preclinical • Journal
|
EGFR (Epidermal growth factor receptor)
|
EGFR mutation • EGFR H1975
|
Tagrisso (osimertinib) • volasertib (NBL-001) • BI2536
1year
Novel Aminopyrimidine-2,4-diones, 2-Thiopyrimidine-4-ones, and 6-Arylpteridines as Dual-Target Inhibitors of BRD4/PLK1: Design, Synthesis, Cytotoxicity, and Computational Studies. (PubMed, Pharmaceuticals (Basel))
MTT assays of synthesized compounds against breast (MDA-MB-231), colorectal (HT-29), and renal (U-937) cancer cells showed excellent-to-good cytotoxic activity, compared to Methotrexate; MDA-MB-231 were the most sensitive cancer cells. It also upregulated the BAX and caspase-3 markers while downregulating the Bcl-2 gene. Finally, active compounds fitted the volasertib binding site at BRD4 and PLK1 and showed ideal drug-like properties and pharmacokinetics, making them promising anticancer candidates.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • PLK1 (Polo Like Kinase 1) • CASP3 (Caspase 3) • BRD4 (Bromodomain Containing 4)
|
methotrexate • volasertib (NBL-001)
1year
Polo-like kinase-1 mediates hepatitis C virus-induced cell migration, a drug target for liver cancer. (PubMed, Life Sci Alliance)
The changes were prevented by treating cells with the PLK1 inhibitor volasertib. In HCV-infected hepatocytes, increased cell motility contributes to cancer cell migration, invasion, and metastasis. PLK1 is an important mediator of these effects and early treatment with PLK1 inhibitors may prevent or reduce HCC progression, particularly in people with HCV-induced HCC.
Journal
|
PLK1 (Polo Like Kinase 1)
|
volasertib (NBL-001)
1year
Pentafuhalol-B, a Phlorotannin from Brown Algae, Strongly Inhibits the PLK-1 Overexpression in Cancer Cells as Revealed by Computational Analysis. (PubMed, Molecules)
Although a variety of anti-cancer drugs, both synthetic and naturally occurring, such as volasertib, onvansertib, thymoquinone, and quercetin, are available either alone or in combination with other therapies, they have limited efficacy, especially in the advanced stages of cancer. Overall, these studies suggest that PtB binds strongly within the pocket sites of PLK-1 through the formation of a stable complex, and also shows higher chemical reactivity than the reference drug volasertib. The present study demonstrated the inhibitory nature of PtB against the PLK-1 protein, establishing its potential usefulness as a small molecule inhibitor for the treatment of different types of cancer.
Journal
|
PLK1 (Polo Like Kinase 1)
|
volasertib (NBL-001) • onvansertib (PCM-075)
1year
BI6727 and GSK461364A, potent PLK1 inhibitors induce G2/M arrest and apoptosis against cholangiocarcinoma cell lines. (PubMed, Pathol Res Pract)
In conclusion, pharmacologic PLK1 inhibition by BI6727 and GSK461364A blocked survival of CCA cells by several mechanisms. Our study provides evidence that BI6727 and GSK461364A could be alternative drugs and have potential implications at the clinical level for CCA therapy.
Preclinical • Journal • PARP Biomarker
|
MCL1 (Myeloid cell leukemia 1) • CASP3 (Caspase 3) • CCNB1 (Cyclin B1)
|
PLK1 overexpression
|
volasertib (NBL-001) • GSK461364
over1year
Reduction-responsive nucleic acid nanocarrier-mediated miR-22 inhibition of PI3K/AKT pathway for the treatment of patient-derived tumor xenograft osteosarcoma. (PubMed, Bioact Mater)
To design and fabricate efficient delivery carriers of miR-22 into osteosarcoma cells, a hydroxyl-rich reduction-responsive cationic polymeric nanoparticle, TGIC-CA (TC), was developed in this work, which also enhanced the therapeutic effects of Volasertib on osteosarcoma...Furthermore, this strategy showed outstanding tumor suppression performance in animal models of orthotopic osteosarcoma, especially in patient-derived chemo-resistant and chemo-intolerant patient-derived xenograft (PDX) models, which reduced the risk of tumor lung metastasis and overcame drug resistance. Therefore, it has great potential for efficient treatment of metastasis and drug resistance of osteosarcoma by the strategy of localized, sustained delivery of miR-22 using the cationic nanocarriers combined with non-traditional chemotherapy drugs.
Journal
|
MIR22 (MicroRNA 22)
|
volasertib (NBL-001)
over1year
Kinome-wide CRISPR-Cas9 knockout screens revealed PLK1 as a therapeutic target for osteosarcoma. (PubMed, Cell Death Discov)
Furthermore, we confirmed that the mode of action (MoA) of volasertib is primarily mediated by the cell-cycle arrest and apoptosis triggered by DNA damage. As PLK1 inhibitors are entering phase III clinical trials, our findings provide important insights into the efficacy and MoA of the relevant therapeutic approach for combating osteosarcoma.
Journal
|
PLK1 (Polo Like Kinase 1)
|
volasertib (NBL-001)
over1year
Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells. (PubMed, J Neurooncol)
The combination of entinostat and PLK1i showed synergistic interaction in vitro, but not in vivo. Therefore, further screening of blood-brain barrier penetrating PLK1i is warranted to determine the true potential of the combination as no on-target activity was observed after PLK1i volasertib treatment in vivo.
Journal
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • PLK1 (Polo Like Kinase 1)
|
volasertib (NBL-001) • Jingzhuda (entinostat)
over1year
Inhibition of PLK1 Destabilizes EGFR and Sensitizes EGFR-Mutated Lung Cancer Cells to Small Molecule Inhibitor Osimertinib. (PubMed, Cancers (Basel))
In conclusion, we describe a novel interaction between mutant EGFR and PLK1 that may be exploited in the clinic. Co-targeting PLK1 and EGFR may improve and prolong the clinical response to EGFR TKI in patients with an EGFR-mutated NSCLC.
Journal
|
EGFR (Epidermal growth factor receptor) • PLK1 (Polo Like Kinase 1)
|
EGFR mutation
|
Tagrisso (osimertinib) • volasertib (NBL-001)
over1year
DHMMF, a natural flavonoid from Resina Draconis, inhibits hepatocellular carcinoma progression via inducing apoptosis and G2/M phase arrest mediated by DNA damage-driven upregulation of p21. (PubMed, Biochem Pharmacol)
Additionally, the combined administration of DHMMF and polo-like kinase 1 (PLK1) inhibitor BI 6727 showed a synergistic anti-HCC efficacy...DHMMF may serve as a promising drug candidate for HCC treatment, especially for patients of HCC with low p21 expression. Our results also suggested that DHMMF treatment in combination with PLK1 inhibitor may serve as a potential treatment strategy for patients with HCC.
Journal
|
CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
volasertib (NBL-001)
over1year
Nano-immunotherapy targeting PD-L1, PLK1, and TLR9 for treatment of non-small cell lung cancer (AACR 2023)
ARAC-02 co-delivers a polo-like kinase 1 (PLK1)-targeted therapy (volasertib), a PD-L1 antibody, and the immune-stimulant CpG...Importantly, intravenous infusions of the platform was also found to be safe in a preliminary toxicology study in non-human primates. Due to its unique ability to catalyze various steps of the adaptive immune response, ARAC-02 is anticipated to provide superior outcomes in NSCLC and a broad range of tumor types regardless of baseline PD-L1 expression.
PD(L)-1 Biomarker • IO biomarker
|
CD8 (cluster of differentiation 8) • PLK1 (Polo Like Kinase 1) • TLR9 (Toll Like Receptor 9)
|
PD-L1 expression • PD-L1 underexpression • PD-L1-L
|
volasertib (NBL-001)
over1year
Anti-CD19 antibody-drug conjugate therapy in B cell non-Hodgkin lymphoma (AACR 2023)
In this study, we developed a Volasertib antibody-drug conjugate (V-ADC) using -CD19 antibody Inebilizumab to increase the targeting specificity for B-cell lymphoma cells and minimize the side effects of Volasertib. In conclusion, starvation and lysosomal cathepsin activation increased V-ADC-induced apoptotic cell death in CD19 overexpression Z138 cell lines. We are actively investigating the in vivo therapeutic effects of V-ADC in patient-derived xenograft (PDX) animal models of MCL and other aggressive B-cell lymphomas.
PARP Biomarker
|
PLK1 (Polo Like Kinase 1) • CASP3 (Caspase 3) • CASP9 (Caspase 9)
|
CD19 expression • CD19 mutation • CD19 overexpression
|
volasertib (NBL-001) • Uplizna (inebilizumab-cdon)
over1year
Inhibition of Polo-like kinase 1 (PLK1) triggers cell apoptosis via ROS-caused mitochondrial dysfunction in colorectal carcinoma. (PubMed, J Cancer Res Clin Oncol)
These data provide new insights into the pathogenesis of CRC and support the potential value of PLK1 as an appealing target for CRC treatment. Overall, the underlying mechanism of inhibiting PLK1-induced apoptosis indicates that the PLK1 inhibitor BI6727 may be a novel potential therapeutic strategy in the treatment of CRC.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • PLK1 (Polo Like Kinase 1)
|
BCL2/BAX ratio elevation
|
volasertib (NBL-001)
almost2years
PLK1 and AURKB phosphorylate survivin differentially to affect proliferation in racially distinct triple-negative breast cancer. (PubMed, Cell Death Dis)
In addition, PLK1 and AURKB inhibition with volasertib and barasertib significantly inhibited the growth of AA TNBC xenografts, but not of EA TNBC tumors. These data suggest that inhibition of PLK1 and AURKB suppresses cell proliferation and tumor growth, specifically in AA TNBC. These findings suggest that targeting survivin phosphorylation may be a viable therapeutic option for AA patients with TNBC.
Journal
|
BIRC5 (Baculoviral IAP repeat containing 5) • PLK1 (Polo Like Kinase 1) • AURKB (Aurora Kinase B)
|
volasertib (NBL-001) • barasertib (AZD1152)
almost2years
In vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in human chordoma xenografts. (PubMed, Front Oncol)
CDK4/6 inhibition appears as a promising strategy to manage advanced chordomas harboring a loss of CDKN2A/2B. However, further preclinical studies are strongly requested to confirm it and to understand acquired or de novo resistance to palbociclib, in the peculiar view of a targeting of the oxidative phosphorylation genes.
Preclinical • Journal
|
CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • PBRM1 (Polybromo 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B)
|
CDKN2A deletion • PBRM1 mutation
|
Ibrance (palbociclib) • volasertib (NBL-001)
almost2years
Targeting of the Polo-like kinase 1 (PLK1) to improve the efficiency of Olaparib in BRCA mutated epithelial ovarian cancer (DKK 2022)
To explore the role of PLK1 in sensitizing EOC cells, OVSAHO and KURAMOCHI, and patient derived 3D-spheroids underwent a mono- or a combination therapy using the PLK1 inhibitor BI6727, the PARP inhibitor Olaparib, and Carboplatin. Our findings elucidate the critical role of PLK1 in the resistance to PARPi in BRCA-mutated EOC and suggest a new combinatorial strategy that may improve platinum-based efficacy.
BRCA Biomarker • PARP Biomarker • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BRCA (Breast cancer early onset) • PLK1 (Polo Like Kinase 1) • CASP3 (Caspase 3) • CASP7 (Caspase 7)
|
BRCA mutation
|
Lynparza (olaparib) • carboplatin • volasertib (NBL-001)
almost2years
Inhibition of DNMT3B and PI3K/AKT/mTOR and ERK Pathways as a Novel Mechanism of Volasertib on Hypomethylating Agent-Resistant Cells. (PubMed, Biomol Ther (Seoul))
Our data suggest that volasertib has a potential role in overcoming HMA resistance in patients with MDS and MDS/ AML by suppressing the expression of DNMT3 enzymes and PI3K/AKT/mTOR and ERK pathways. We also found that DNMT3B overexpression might be associated with resistance to volasertib.
Journal
|
PLK1 (Polo Like Kinase 1) • DNMT1 (DNA methyltransferase 1) • DNMT3B (DNA Methyltransferase 3 Beta)
|
DNMT3B overexpression
|
volasertib (NBL-001)
2years
Targeting PLK1 As a Novel Strategy for Acute Myeloid Leukemias with Fanconi Anemia Pathway Mutations (ASH 2022)
The clinical success of PLK1 inhibitors, such as volasertib and onvansertib, has been limited by the absence of predictive biomarkers of response and adverse side effects. Together, these findings indicate that PLK1 inhibition causes damage to mitotic chromosomes and subsequent activation of the FA pathway. Our work identifies a mitosis-specific vulnerability of FA-deficient cells and suggests that genetic disruptions of the FA pathway may be predictive of sensitivity to PLK1 inhibition, providing a preclinical rationale for the development of precision therapies.
BRCA Biomarker
|
BRCA1 (Breast cancer 1, early onset) • FANCA (FA Complementation Group A) • PLK1 (Polo Like Kinase 1) • CHEK1 (Checkpoint kinase 1) • FANCD2 (FA Complementation Group D2) • FANCG (FA Complementation Group G) • BUB1 (BUB1 Mitotic Checkpoint Serine/Threonine Kinase)
|
FANCA mutation
|
volasertib (NBL-001) • onvansertib (PCM-075)
2years
A Novel Role for PLK1 in Leukemia Stem Cell Function in Acute Myeloid Leukemia (ASH 2022)
To determine the effects of PLK1 against LSCs in vivo, we carried out PLK1 inhibitor treatment using the specific PLK1 inhibitor volasertib in a cohort of 9 primary AML samples in PDX models...Our study highlights PLK1 as a specific vulnerability of LSCs, and furthers the understanding of malignant PLK1 signaling in non-cell cycle related processes. Further insights into the underlying mechanisms will enable the development of effective therapies to target these pathways and improve patient outcomes in AML.
IO biomarker
|
CD34 (CD34 molecule) • PLK1 (Polo Like Kinase 1)
|
volasertib (NBL-001)
2years
Pre-Clinical Evaluation of a Camsirubicin Analog Mnpr-202 in Diffuse Large B Cell Lymphoma (ASH 2022)
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of aggressive lymphoma, for which the standard-of-care treatment is rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP)...For example, a clear antagonistic effect on cell killing was seen between PLK1 inhibitor, volasertib, and doxorubicin, but between volasertib and MNPR-202, this antagonism was seen to a significantly lesser extent...These intracellular differences also influence drug synergies observed with the two chemotherapeutics, implying that in the context of certain combinatorial regimens, MNPR-202 may be superior to doxorubicin. Overall these findings suggest promise for further in vivo and clinical evaluation of MNPR-202 as a potentially effective yet non-cardiotoxic anthracycline derivative in lymphoma.
Preclinical
|
STING (stimulator of interferon response cGAMP interactor 1)
|
Rituxan (rituximab) • cyclophosphamide • vincristine • prednisone • volasertib (NBL-001) • MNPR-202 • camsirubicin (MNPR-201)
2years
A Multiomic Approach to Reversing Therapy Resistance in Multiple Myeloma Using Paired Ex Vivo Drug Sensitivity Measures and RNA Sequencing Data (ASH 2022)
Ex vivo functional validation in a cohort of 61 MM patient samples shows a statistically significant (unpaired t-test) lowering of Volasertib (PLK1 inhibitor) AUC in MM patients that were clinically refractory to CFZ (p-value = 0.03) and BTZ (p-value = 0.02) compared to PI-naïve (Figure 2)...Ongoing studies are focused on identifying novel targets to overcome resistance to DARA. The proposed computational approach can identify novel therapeutic strategies to overcome SOC therapy resistance using patient-specific targeted therapies.
Preclinical
|
SDC1 (Syndecan 1) • FOXM1 (Forkhead Box M1)
|
volasertib (NBL-001)
2years
BI6727, a polo-like kinase 1 inhibitor, synergizes with gefitinib to suppress hepatocellular carcinoma cells via a G2/M arrest mechanism. (PubMed, Pharmazie)
In summary, the present study discovered that gefitinib synergizing with BI6727 could significantly facilitate DNA damage and overcome acquired resistance of HCC cells to gefitinib. Our study provides a promising approach for the combination of EGFR inhibitors and PLK1 inhibitors in the clinical treatment for HCC.
Journal
|
PLK1 (Polo Like Kinase 1) • CDC25C (Cell Division Cycle 25C) • GNRP (Ras-Specific Guanine Nucleotide-Releasing Factor 1)
|
gefitinib • volasertib (NBL-001)
2years
Transferrin-guided intelligent nanovesicles augment the targetability and potency of clinical PLK1 inhibitor to acute myeloid leukemia. (PubMed, Bioact Mater)
PLK1 inhibitor, volasertib (Vol), is among the few molecular targeted drugs granted breakthrough therapy status for AML; however, its fast clearance and dose-limiting toxicity greatly restrain its clinical benefits...The efficacy studies in orthotopic MV-4-11 leukemic model demonstrated that TPVol significantly reduced leukemic cell proportions in periphery blood, bone marrow, liver and spleen, effectively enhanced mouse survival rate, and impeded bone loss. This transferrin-guided nano-delivery of molecular targeted drugs appears to be an interesting strategy towards the development of novel treatments for AML.
Journal
|
PTEN (Phosphatase and tensin homolog)
|
volasertib (NBL-001)