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    4ms
    ONC201/TIC10 plus TLY012 anti-cancer effects via apoptosis inhibitor downregulation, stimulation of integrated stress response and death receptor DR5 in gastric adenocarcinoma. (PubMed, Am J Cancer Res)
    Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.
    Journal • PARP Biomarker
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    HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MLH1 (MutL homolog 1) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • CASP3 (Caspase 3) • CASP8 (Caspase 8) • XIAP (X-Linked Inhibitor Of Apoptosis) • ATF4 (Activating Transcription Factor 4) • CFLAR (CASP8 and FADD-like apoptosis regulator)
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    TP53 mutation • KRAS mutation • HER-2 amplification • PIK3CA mutation • MLH1 mutation
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    nesuparib (JPI-547) • dordaviprone (ONC201)
    1year
    JPI-547, a novel dual inhibitor of PARP 1/2 and tankyrase 1/2 overcomes olaparib resistance in BRCA 1/2 mutant ovary and breast cancer preclinical model (AACR 2023)
    Using established olaparib resistance models, the anti-tumor efficacy of JPI-547 was compared with olaparib, niraparib, and talazoparib. Then this suppression resulted in blockade of HR repair.JPI-547 showed promising efficacy in an olaparib-resistant preclinical model. JPI-547 merits further clinical development in the PARP inhibitor-resistant ovary and breast cancer.
    Preclinical • BRCA Biomarker • PARP Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • BRCA (Breast cancer early onset) • RAD51 (RAD51 Homolog A)
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    BRCA2 mutation • BRCA1 mutation • BRCA mutation
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    Lynparza (olaparib) • Talzenna (talazoparib) • Zejula (niraparib) • nesuparib (JPI-547)
    1year
    JPI-547, a dual inhibitor of PARP/Tankyrase, shows promising antitumor activity against pancreatic cancers with homologous recombination repair deficiency or Wnt-addiction (AACR 2023)
    JPI-547 is a novel PARP inhibitor, simultaneously targeting tankyrase1/2, other members of the PARP family, that are involved in the Wnt/β-catenin pathway. Antiproliferative effect of JPI-547 and a variety of PARP inhibitors (olaparib, veliparib, talazoparib, niraparib, and rucaparib) were determined by MTT assay or clonogenic assay in 9 human pancreatic ductal adenocarcinoma (PDAC) cell lines (Capan-1, HPAF-II, Capan-2, AsPC-1, SNU-410, SNU-213, SNU-324, MIA-PaCa2, and PANC-1). JPI-547 shows promising, preclinical antitumor effects against PDAC cells with HRD or Wnt-addiction, providing a rationale for further biomarker-driven clinical development of JPI-547 for the treatment of patients with PDAC.
    BRCA Biomarker • PARP Biomarker
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    BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • RNF43 (Ring Finger Protein 43)
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    HRD • RNF43 mutation
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    Lynparza (olaparib) • Talzenna (talazoparib) • Zejula (niraparib) • Rubraca (rucaparib) • veliparib (ABT-888) • nesuparib (JPI-547)
    1year
    Imipridones ONC201 and ONC206 reduce expression of neogenin and EZH1/2 which correlate with synergy following their combination with EZH1/2 or HDAC inhibitors in treatment of DMG and other tumors (AACR 2023)
    The effective CI of ONC206 plus tazemetostat and panobinostat ranges 0.27-0.77 in U251 GBM and 0.11-0.71 in SU-DIPG-13 DMG cells...The effective CI of ONC212 plus valemetostat ranges 0.33-0.83 in 22Rv1...The synergies between ONC201 and EZH1/2 or HDAC inhibitors provide clues for developing novel therapy for the mentioned tumors. Overexpression of EZH2 is in process to elucidate the role of EZH2 in the mechanism of the anti-cancer effect of ONC201.
    PARP Biomarker
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    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)
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    EZH2 mutation • EZH2 overexpression
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    Tazverik (tazemetostat) • Farydak (panobinostat) • nesuparib (JPI-547) • dordaviprone (ONC201) • Ezharmia (valemetostat) • ONC212 • ONC206
    1year
    PARP inhibitor rucaparib in combination with imipridones ONC201 or ONC212 demonstrates preclinical synergy against BRCA1/2-deficient breast, ovarian, and prostate cancer cells (AACR 2023)
    Our lab previously showed efficacy of imipridone ONC201 in BRCA-deficient cancer cells and potential synergy with olaparib (2017 AACR annual meeting abstract), without further investigating potential synergistic mechanisms...Further studies are ongoing to characterize possible mechanisms and effects of PARP inhibitor-imipridone combination treatment on immune-mediated killing. Our findings identify novel PARP inhibitor-imipridone therapy combinations that can be further developed for treatment of BRCA1/2 deficient cancers.
    Preclinical • Combination therapy • BRCA Biomarker • PARP Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • BRCA (Breast cancer early onset) • ATF4 (Activating Transcription Factor 4)
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    BRCA2 mutation • BRCA1 mutation
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    Lynparza (olaparib) • Rubraca (rucaparib) • nesuparib (JPI-547) • dordaviprone (ONC201) • ONC212
    1year
    Synergistic activity of ABT-263 and ONC201/TIC10 against solid tumor cell lines is associated with suppression of anti-apoptotic Mcl-1, BAG3, pAkt, and upregulation of pro-apoptotic Noxa and Bax cleavage during apoptosis. (PubMed, Am J Cancer Res)
    Our data provide evidence for synergy from the combination of ONC201 and ABT-263 against human solid tumor cell lines associated with alterations in cell death and pro-survival mediators. The combination of ONC201 and ABT-263 merits further exploration in vivo and in clinical trials against a variety of solid malignancies.
    Preclinical • Journal • Tumor cell
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    MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • ATF4 (Activating Transcription Factor 4)
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    navitoclax (ABT 263) • nesuparib (JPI-547) • dordaviprone (ONC201)
    almost2years
    A Study to Evaluate the Efficacy and Safety of JPI-547 in Platinum-resistant, Advanced/Relapsed Ovarian Cancer Subjects Previously Treated With a PARP Inhibitor (clinicaltrials.gov)
    P2, N=58, Not yet recruiting, Onconic Therapeutics Inc.
    New P2 trial
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)
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    BRCA2 mutation • BRCA1 mutation
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    nesuparib (JPI-547)