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  • ||||||||||  Journal:  Activation of the integrated stress response by inhibitors of its kinases. (Pubmed Central) -  Sep 13, 2023   
    The tyrosine kinase inhibitors Neratinib and Dovitinib also activate GCN2 by increasing affinity of GCN2 for ATP. Thus, the mechanism uncovered here might be broadly relevant to ATP-competitive inhibitors and perhaps to other kinases.
  • ||||||||||  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.
  • ||||||||||  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.
  • ||||||||||  Jingzhuda (entinostat) / Syndax Pharma, EOC Pharma
    Journal:  Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells. (Pubmed Central) -  Jun 2, 2023   
    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.
  • ||||||||||  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.
  • ||||||||||  Lynparza (olaparib) / Merck (MSD), AstraZeneca
    Targeting of the Polo-like kinase 1 (PLK1) to improve the efficiency of Olaparib in BRCA mutated epithelial ovarian cancer () -  Nov 30, 2022 - Abstract #DKK2022DKK_2132;    
    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.
  • ||||||||||  Patient-Derived Organoids and Their Potential for Precision Medicine in Neuroendocrine Tumors () -  Nov 8, 2022 - Abstract #NANETS2022NANETS_163;    
    Tumor heterogeneity may be contributing to the differences seen in the drug response between the three NET organoids and requires further evaluation. Replication of these studies in a larger subset of patient samples and drug combination studies will be important for the advancement of therapeutics in NETs.
  • ||||||||||  dovitinib (TKI258) / Allarity Therap, Oncoheroes
    Journal:  DNA-Encoded Library Screening To Inform Design of a Ribonuclease Targeting Chimera (RiboTAC). (Pubmed Central) -  Nov 8, 2022   
    Conversion of Dovitinib into this RiboTAC reprograms the known drug to selectively affect the RNA target. This work demonstrates that DEL can be used to identify compounds that bind and recruit proteins with effector functions in heterobifunctional compounds.
  • ||||||||||  onvansertib (PCM-075) / Cardiff Oncology, volasertib (NBL-001) / Oncoheroes, Notable Labs
    Targeting PLK1 As a Novel Strategy for Acute Myeloid Leukemias with Fanconi Anemia Pathway Mutations (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_4204;    
    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.
  • ||||||||||  camsirubicin (MNPR-201) / Monopar Therap, MNPR-202 / National University of Singapore, Monopar Therap
    Pre-Clinical Evaluation of a Camsirubicin Analog Mnpr-202 in Diffuse Large B Cell Lymphoma (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_4098;    
    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.
  • ||||||||||  volasertib (NBL-001) / Oncoheroes, Notable Labs
    A Novel Role for PLK1 in Leukemia Stem Cell Function in Acute Myeloid Leukemia (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_4058;    
    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.
  • ||||||||||  volasertib (NBL-001) / Oncoheroes, Notable Labs
    A Multiomic Approach to Reversing Therapy Resistance in Multiple Myeloma Using Paired Ex Vivo Drug Sensitivity Measures and RNA Sequencing Data (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_2712;    
    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.
  • ||||||||||  stenoparib (2X-121) / Allarity Therap, Oncoheroes
    Trial completion date, Trial primary completion date, Metastases:  PREDICT 2X-121: Investigation of 2X-121 in Patients With Advanced Ovarian Cancer Selected by the 2X-121 DRP® (clinicaltrials.gov) -  Oct 11, 2022   
    P2,  N=60, Recruiting, 
    Our study provides a promising approach for the combination of EGFR inhibitors and PLK1 inhibitors in the clinical treatment for HCC. Trial completion date: Mar 2023 --> Mar 2024 | Trial primary completion date: Sep 2022 --> Sep 2023
  • ||||||||||  volasertib (NBL-001) / Oncoheroes, Notable Labs
    Journal:  Transferrin-guided intelligent nanovesicles augment the targetability and potency of clinical PLK1 inhibitor to acute myeloid leukemia. (Pubmed Central) -  Oct 4, 2022   
    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.
  • ||||||||||  tozasertib (MK-0457) / Merck (MSD), volasertib (BI 6727) / Oncoheroes, Notable Labs
    Biomarker, Journal, Tumor microenvironment:  Single-cell profiling reveals molecular basis of malignant phenotypes and tumor microenvironments in small bowel adenocarcinomas. (Pubmed Central) -  Sep 20, 2022   
    Especially, we predicted specific drugs for SBA based on differential gene expression signatures between malignant cells and normal epithelial cells of SBA, and verified more potent inhibitory effects of volasertib and tozasertib for SBA cancer cells than conventional drugs of SBA at the same concentration, which provides new clues for treatments of SBA. In summary, our study provides a blueprint of the molecular signatures of both tumor cells and tumor microenvironment cells in SBA and reveals potential targets and drug candidates for its clinical treatments.
  • ||||||||||  stenoparib (2X-121) / Allarity Therap, Oncoheroes
    Preclinical, Journal:  Stenoparib, an inhibitor of cellular poly (ADP-ribose) polymerases (PARPs), blocks in vitro replication of SARS-CoV-2 variants. (Pubmed Central) -  Sep 20, 2022   
    Here we show that stenoparib effectively inhibits a SARS-CoV-2 wild type (BavPat1/2020) strain and four additional variant strains; alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2) and gamma (P.1) in vitro, with 50% effective concentration (EC50) estimates of 4.1 μM, 8.5 μM, 24.1 μM, 8.2 μM and 13.6 μM, respectively. A separate experiment focusing on a combination of 10 μM stenoparib and 0.5 μM remdesivir, an antiviral drug, resulted in over 80% inhibition of the alpha variant, which is substantially greater than the effect achieved with either drug alone, suggesting at least additive effects from combining the different mechanisms of activity of stenoparib and remdesivir.
  • ||||||||||  Herceptin (trastuzumab) / Roche, volasertib (BI 6727) / Oncoheroes, Notable Labs
    Journal:  HER-2-mediated nano-delivery of molecular targeted drug potently suppresses orthotopic epithelial ovarian cancer and metastasis. (Pubmed Central) -  Sep 14, 2022   
    Anti-HER-2 antibody, trastuzumab (Tra), was conjugated onto Vol-loaded polymersomes via click chemistry yielding Tra-PVol with a size of 33 nm and optimally about 5 Tra per polymersome...More interestingly, Tra-PVol was shown to effectively suppress the intraperitoneal metastasis and to markedly prolong the survival time of SKOV-3-Luc tumor-bearing mice. This HER-2 directed molecular therapy emerges as a potential treatment strategy toward EOC.
  • ||||||||||  volasertib (BI 6727) / Oncoheroes, Notable Labs
    Review, Journal:  Polo-like Kinase 1 Inhibitors in Human Cancer Therapy: Development and Therapeutic Potential. (Pubmed Central) -  Aug 14, 2022   
    To date, at least 10 PLK1 inhibitors (PLK1i) have been entered into clinical trials, among which the typical kinase domain (KD) inhibitor BI 6727 (volasertib) was granted "breakthrough therapy designation" by the FDA in 2013...Researchers recently discovered many PLK1i with higher selectivity, stronger potency, and better absorption, distribution, metabolism, and elimination (ADME) characteristics. In this review, we emphasize the structure-activity relationships (SARs) of PLK1i, providing insights into new drugs targeting PLK1 for antitumor clinical practice.
  • ||||||||||  TriptoSar (triptolide) / Pierre Fabre, dovitinib (TKI258) / Allarity Therap, Oncoheroes
    Journal:  How to avoid misinterpretation of dual reporter gene assay data affected by cell damage. (Pubmed Central) -  Jul 30, 2022   
    Finally, a step-by-step guide is proposed to avoid misleading set-up of the assay or misinterpretation of the data obtained. Key considerations here include (1) omission of drug concentrations beyond 10-20% proliferation inhibition; (2) observation of Renilla luminescence, because this tends to indicate 'false PXR activation' when it inexplicably decreases; (3) parallel decrease of relative PXR activity and proliferation below baseline levels in conjunction with a sharp decrease in Renilla luminescence indicates 'false PXR antagonism'; (4) non-sigmoidal relationships suggest the absence of concentration dependency.
  • ||||||||||  volasertib (BI 6727) / Oncoheroes, Notable Labs
    Journal, PD(L)-1 Biomarker, IO biomarker:  Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment. (Pubmed Central) -  Jul 27, 2022   
    ARAC is a nanoparticle co-delivering PLK1 inhibitor (volasertib) and PD-L1 antibody...ARAC also shows efficacy in another lung tumor model (KLN-205), which does not respond to CTLA-4 and PD-1 inhibitor combination. This study highlights a rational combination strategy to augment existing therapies by utilizing our nanoparticle platform that can load multiple cargo types at once.