- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs
Journal: KIF2A Upregulates PI3K/AKT Signaling through Polo-like Kinase 1 (PLK1) to Affect the Proliferation and Apoptosis Levels of Eriocheir sinensis Spermatogenic Cells. (Pubmed Central) - Mar 27, 2024
In this study, we knocked down the Es-Kif2a gene by injecting dsRNA into E. sinensis and inhibited Es-Plk1 gene expression by injecting PLK1 inhibitor BI6727 into E. sinensis...Western Blot showed that the expression of Es-PLK1 decreased after Es-Kif2a knockdown, while there was no significant change of Es-KIF2A after Es-Plk1 inhibition, indicating that Es-PLK1 may be a downstream factor of Es-KIF2A. Taken together, these results suggest that Es-KIF2A upregulates the PI3K/AKT signaling pathway through Es-PLK1 during the spermatogenesis of E. sinensis, thereby affecting the proliferation and apoptosis levels of spermatogenic cells.
- |||||||||| Xalkori (crizotinib) / Pfizer, dovitinib (TKI258) / Allarity Therap, Oncoheroes
Biomarker, Journal: TBX15 and SDHB expression changes in colorectal cancer serve as potential prognostic biomarkers. (Pubmed Central) - Mar 22, 2024
Our findings highlight the potential association between alterations in the expression of genes such as HOXC6, HOXC13, HOXC8, TBX15, SDHB, COX5A, and UQCRC1 and increased mortality rates in CRC patients. As revealed by the PPI network, these genes exhibited the most connections with other genes linked to survival.
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs
PLK1 predicts aggressive behavior in CRC patients and its inhibition reverse chemoresistance in CRC cells (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_8044;
To explore the role of PLK1 on chemoresistance, we inhibited PLK1 using specific inhibitor, volasertib and we showed that volasertib effectively reversed 5-Fu resistance in these cells...In addition, we showed that silencing of ERK1/2 reversed the chemoresistance, EMT and stemness of PLK1 expressing CRC cell lines. Our findings underscore the significant role of PLK1 in conferring chemoresistance, and targeting PLK1 could represent a viable therapeutic approach for the treatment of patients with an aggressive subtype of CRC.
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs
VGLL1-derived peptides demonstrated anticancer effect by inhibiting VGLL1-TEAD4 interaction (Section 27) - Mar 5, 2024 - Abstract #AACR2024AACR_7961;
We also found that SCVP in combination and the PLK inhibitor volasertib resulted in a synergistic effect on the growth inhibition of breast cancer cells. In conclusion, we demonstrated VGLL1 as a novel target for anticancer drug development, and elucidated the molecular mechanism and therapeutic potential of the SCVP in gastric and breast cancers.
- |||||||||| thiostrepton (RSO-021) / RS Oncology, volasertib (NBL-001) / Oncoheroes, Notable Labs
The co-targeting of PLK1 and FoxM1 contributes to synergistic antitumor effects in PTC (Section 25) - Mar 5, 2024 - Abstract #AACR2024AACR_6689;
The combined inhibition of PLK1 with volasertib and FoxM1 with thiostrepton synergistically attenuated PTC cell growth in vitro and in vivo. Our findings suggest that co-targeting of PLK1 and FoxM1 could be a viable therapeutic strategy for treating patients with an aggressive subtype of PTC.
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs
Preclinical, Journal: Tangeretin attenuates acute lung injury in septic mice by inhibiting ROS-mediated NLRP3 inflammasome activation via regulating PLK1/AMPK/DRP1 signaling axis. (Pubmed Central) - Jan 10, 2024
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. TAN attenuates sepsis-induced ALI by inhibiting ROS-mediated NLRP3 inflammasome activation via regulating PLK1/AMPK/DRP1 signaling axis, and TAN is a potentially therapeutic candidate against ALI through inhibiting pyroptosis.
- |||||||||| BI2536 / Boehringer Ingelheim, BHG712 / Novartis, volasertib (NBL-001) / Oncoheroes, Notable Labs
Journal: Eph signal inhibition potentiates the growth-inhibitory effects of PLK1 inhibition toward cancer cells. (Pubmed Central) - Jan 8, 2024
These results suggest that Eph signal inhibition potentiates the effect of PLK1 inhibition, leading to strong mitotic arrest via SAC activation and the subsequent reduction of cancer cell survival. The combination of PLK1 inhibition and Eph signal inhibition will provide a new effective strategy for targeting cancer cell division.
- |||||||||| dovitinib (TKI258) / Allarity Therap, Oncoheroes
Journal: Identification of promising small-molecule inhibitors targeting STK17B for cancer therapeutics: molecular docking and molecular dynamics investigations. (Pubmed Central) - Dec 26, 2023
Ligand-based virtual screening and molecular docking were performed, resulting in the selection of three lead compounds (CID_135698391, CID_135453100, CID_136599608) with superior binding affinities compared to the reference compound dovitinib...Overall, small-molecule compounds CID_135453100 and CID_136599608 showed promising binding interactions and stability, suggesting their potential as direct inhibitors of STK17B. These findings could contribute to the exploration of novel therapeutic options targeting STK17B in cancer treatment.Communicated by Ramaswamy H. Sarma.
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs
Journal: Polo-like kinase 1 promotes sepsis-induced myocardial dysfunction. (Pubmed Central) - Nov 20, 2023
Inhibition of Plk-1 either by heterozygous deletion of Plk-1 or Plk-1 inhibitor BI 6727 alleviated LPS-induced myocardial injury, inflammation, cardiac dysfunction, and thereby improved the survival of LPS-treated mice...Plk-1 inhibition impeded NF-?B signal pathway activation in LPS-treated mouse hearts and NRCMs. Augmented Plk-1 is thus essential for the development of SIMD and is a druggable target for SIMD.
- |||||||||| dovitinib (TKI258) / Allarity Therap, Oncoheroes
Journal: Optimization of a Protein-Targeted Medicine into an RNA-Specific Small Molecule. (Pubmed Central) - Nov 20, 2023
In this study, we use knowledge of the molecular recognition of both protein and RNA targets by dovitinib to design molecules that specifically inhibit the RNA target but lack activity against canonical protein targets in cells. As it is now becoming apparent that RNA can be both an on- and off-target for small molecule medicines, this study lays a foundation to use design principles to maximize desired compound activity while minimizing off-target effects.
- |||||||||| Nexletol (bempedoic acid) / Esperion Therap, Otsuka, Daiichi Sankyo, volasertib (NBL-001) / Oncoheroes, Notable Labs
Journal, Pan tumor: Combined Inhibition of UBE2C and PLK1 Reduce Cell Proliferation and Arrest Cell Cycle by Affecting ACLY in Pan-Cancer. (Pubmed Central) - Nov 18, 2023
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.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, alisertib (MLN8237) / Puma, volasertib (NBL-001) / Oncoheroes, Notable Labs
Resistance to Targeted Anti-Mitotics in Glioblastoma is Driven by STAT3 Activation and Therapy Induced Senescence (Exhibit Hall A/B) - Nov 11, 2023 - Abstract #SNO2023SNO_610;
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. We reported (Kenchappa et al., Cell Reports, 2022) that resistance to one of these
- |||||||||| Journal: Drug repurposing analysis for colorectal cancer through network medicine framework: Novel candidate drugs and small molecules. (Pubmed Central) - Nov 3, 2023
Based on the gene module, polyethylene glycol, gallic acid, pyrazole, cordycepin, phenothiazine, pantoprazole, cysteamine, indisulam, valinomycin, trametinib, BRD-K81473043, AZD8055, dovitinib, BRD-A17065207, and tyrphostin AG1478 presented as drugs and small molecule candidates previously studied in the CRC. Lornoxicam, suxamethonium, oprelvekin, sirukumab, levetiracetam, sulpiride, NVP-TAE684, AS605240, 480743.cdx, HDAC6 inhibitor ISOX, BRD-K03829970, and L-6307 are proposed as novel drugs and small molecule candidates for CRC.
- |||||||||| Tagrisso (osimertinib) / AstraZeneca
Journal: The effect of PLK1 inhibitor in osimertinib resistant non-small cell lung carcinoma cells. (Pubmed Central) - Oct 30, 2023
Lornoxicam, suxamethonium, oprelvekin, sirukumab, levetiracetam, sulpiride, NVP-TAE684, AS605240, 480743.cdx, HDAC6 inhibitor ISOX, BRD-K03829970, and L-6307 are proposed as novel drugs and small molecule candidates for CRC. 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.
- |||||||||| dovitinib (TKI258) / Allarity Therap, Oncoheroes
Journal: Targeting UBR5 inhibits postsurgical breast cancer lung metastases by inducing CDC73 and p53 mediated apoptosis. (Pubmed Central) - Oct 19, 2023
Transcriptome analyses revealed a prominent role of the p53 pathway in dovitinib-induced apoptosis of tumor cells differentially regulated by UBR5 and CDC73...Furthermore, a xenograft model of human TNBC recapitulated the metastatic properties and characteristics of the unique UBR5-CDC73 functional antagonism. This study reveals the novel and critical roles and intricate relationships of UBR5, CDC73 and p53 in postsurgical breast cancer metastasis and indicates the potential of targeting this pathway in cancer therapy.
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs
Only infantile MLL rearranged leukemia is susceptible to a Volasertib treatment by inhibition of PLK-1 (X4) - Sep 30, 2023 - Abstract #DGHO2023DGHO_1441;
Our genome editing approach provides an experimental platform to compare side-by-side new targeted therapies by considering variables such as the cell of origin. PLK-1 inhibitor Volasertib shows the most promising anti-tumor effects in MLL-AF9 cells derived from CB appearing to be a potential new therapeutic strategy to improve the poor outcome of infant MLL- rearranged leukemia.
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs
Journal, IO biomarker: 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 Central) - Sep 28, 2023
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.
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs
Journal: Reduction-responsive nucleic acid nanocarrier-mediated miR-22 inhibition of PI3K/AKT pathway for the treatment of patient-derived tumor xenograft osteosarcoma. (Pubmed Central) - Jul 31, 2023
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.
- |||||||||| stenoparib (2X-121) / Allarity Therap, Oncoheroes
Trial completion date, Trial primary completion date, Metastases: Investigation of Anti-tumour Effect and Tolerability of the PARP Inhibitor 2X-121 in Patients With Metastatic Breast Cancer Selected by the 2X-121 DRP (clinicaltrials.gov) - Jul 20, 2023
P2, N=30, Active, not recruiting,
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. Trial completion date: May 2023 --> May 2024 | Trial primary completion date: Apr 2023 --> Apr 2024
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs
Journal: Kinome-wide CRISPR-Cas9 knockout screens revealed PLK1 as a therapeutic target for osteosarcoma. (Pubmed Central) - Jul 8, 2023
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Walter and Eliza Hall Institute, PHA665752 / Pfizer, dovitinib (TKI258) / Allarity Therap, Oncoheroes
Journal, IO biomarker: Combined immune and DDR pathway classifier: A novel pathway-based classification aimed at tailoring personalized therapies for acute myeloid leukemia patients. (Pubmed Central) - Jun 19, 2023
Moreover, single-cell analysis revealed that there are more immune cells clustered in the IMDDR subtype and higher number of monocyte-like cells, which exert immunosuppressive effects, in the IMDDR subtype. These findings can be applied for molecular stratification of patients and might contribute to the development of personalized targeted therapies for AML.
- |||||||||| 3D-EXplore platform of fresh patient tumoroids with intact TME allows assessment of the efficacy of drugs targeting the tumor stroma on ex vivo tumor immunotherapy (Section 2; Poster Board #3) - Mar 14, 2023 - Abstract #AACR2023AACR_7696;
Treatment-mediated changes in the tumor immune microenvironment was furthercorroborated by a multiplex cytokine release assay detecting GM-CSF, sCD137, IFN?, sFas,sFasL, Granzyme A, Granzyme B, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, MIP-1?, MIP-1?, TNF-?,Perforin in tumoroid culture media and correlated with clinicopathologic findings and PD-L1expression for individual tumnors. Further, this 3D-tumoroid platform provides unique insightinto the microenvironment of both treatment responsive and non-responsive tumors and can aidin the development of patient-centered therapeutic regimens.
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs
Nano-immunotherapy targeting PD-L1, PLK1, and TLR9 for treatment of non-small cell lung cancer (Section 22; Poster Board #22) - Mar 14, 2023 - Abstract #AACR2023AACR_7456;
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.
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs, Zelboraf (vemurafenib) / Roche
PLK1 promotes the metastasis and drug resistance in melanoma (Section 17; Poster Board #10) - Mar 14, 2023 - Abstract #AACR2023AACR_7173;
Our in vitro and in vivo experiments have shown an improved efficacy of this combined therapy on inhibition of cell proliferation, induction of cell death, and suppression of cell metastasis compared to mono-treatment. In short, our data has indicated PLK1 as a potent and promising target in cancer treatment.
- |||||||||| onvansertib (PCM-075) / Cardiff Oncology, volasertib (NBL-001) / Oncoheroes, Notable Labs
Targeting PLK1 effectively suppresses growth of small cell lung cancer (Section 17; Poster Board #8) - Mar 14, 2023 - Abstract #AACR2023AACR_7171;
Volasertib achieved significant tumor growth inhibition relative to control in H526 xenografts...The combination of PLK1i with standard chemotherapeutic agents identified promising synergy of the combination of onvansertib and paclitaxel...CRISPR knockout of YAP1 in this cell line enhanced SW1271 sensitivity to PLK1i suggesting that YAP1 expression as a marker of vulnerability to PLK1i could be context dependent especially when co-occurring with TP53 mutations. The mechanism of this interaction will be discussed.
- |||||||||| Uplizna (inebilizumab) / Horizon Therapeutics, Mitsubishi Tanabe, volasertib (NBL-001) / Oncoheroes, Notable Labs
Anti-CD19 antibody-drug conjugate therapy in B cell non-Hodgkin lymphoma (Section 13; Poster Board #23) - Mar 14, 2023 - Abstract #AACR2023AACR_4879;
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.
- |||||||||| BI2536 / Boehringer Ingelheim, volasertib (NBL-001) / Oncoheroes, Notable Labs
Preclinical examination of PLK1 inhibitors for the treatment of diffuse midline gliomas (Section 15; Poster Board #9) - Mar 14, 2023 - Abstract #AACR2023AACR_3842;
Together, these data indicate that targeting PLK1 is a highly promising therapeutic strategy to arrest DMG tumorgenicity. This data has formed the basis for a planned international Phase 1/2 trial of the PLK1 inhibitor volasertib in combination with radiotherapy in paediatric patients with DMG.
- |||||||||| LY294002 / Eli Lilly, dovitinib (TKI258) / Allarity Therap, Oncoheroes
Journal, Machine learning: The combination of machine learning and transcriptomics reveals a novel megakaryopoiesis inducer, MO-A, that promotes thrombopoiesis by activating FGF1/FGFR1/PI3K/Akt/NF-?B signaling. (Pubmed Central) - Mar 7, 2023
Similarly, inhibition of PI3K-Akt signal pathway by its inhibitor LY294002 suppressed MK differentiation, and PI3K, Akt and NF-?B phosphorylation induced by MO-A. Taken together, our study provides an efficient drug discovery strategy for hematological diseases, and demonstrates that MO-A is a novel countermeasure for treating RIT through activation of the FGF1/FGFR1/PI3K/Akt/NF-?B signaling pathway.
- |||||||||| dovitinib (TKI258) / Allarity Therap, Oncoheroes, stenoparib (2X-121) / Allarity Therap, Oncoheroes
Trial initiation date, Combination therapy, Monotherapy, Metastases: Study to Determine the Maximum Tolerated Dose (MTD) of PARPi 2X-121 Monotherapy and the MTD of Dovitinib in Combination With 2X-121 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - Feb 2, 2023
P1, N=40, Recruiting,
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. Initiation date: Oct 2022 --> Feb 2023
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