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作者: Andreeff, Michael ; Al-Mulla, Fahd ; Olson, Gary L. ; Lim, Bora ; Zhou, Lanlan ; Borthakur, Gautam ; Stein, Mark ; Dicker, David T. ; Wu, Gen Sheng ; Allen, Joshua E. ; Lev, Avital ; Oster, Wolfgang ; Lulla, Amriti ; Bertino, Joseph ; El-Deiry, Wafik S. ; Prabhu, Varun V. ; Kline, C. Leah B. ; Schalop, Lee ; Madhukar, Neel ; Talekar, Mala K. ; Baumeister, Marie ; Kaufman, Howard L. ; Wang, Michael L. ; Elemento, Olivier ; Nallaganchu, B. Rao ; Duvic, Madeleine ; Pottorf, Richard S. ; Benes, Cyril ; Flaherty, Keith ; Wagner, Jessica ; Stogniew, Martin ; Ishizawa, Jo

[This corrects the article DOI: 10.18632/oncotarget.11814.].

2019-09-01·Journal of Autoimmunity1区 · 医学

HLA-DR15-specific inhibition attenuates autoreactivity to the Goodpasture antigen

1区 · 医学

Article

作者: Kitching, A Richard ; Eggenhuizen, Peter J ; Sun, Yanjun ; Rao, N Bhaskara ; Holdsworth, Stephen R ; Self, Christopher R ; Olson, Gary L ; Ooi, Joshua D ; Huynh, Megan

Goodpasture's disease manifests as rapidly progressive glomerulonephritis. Current immunosuppressive treatments do not specifically target the pathological immune response and have significant side effects. Like most autoimmune diseases, the strongest genetic association is with the HLA alleles. Inheritance of HLA-DR15 confers susceptibility, and structure-function studies have shown that HLA-DR15 plays a causative role in activating autoreactive pro-inflammatory T cells. Thus, specific inhibition of HLA-DR15 would provide a targeted therapeutic approach. We hypothesised that PV-267, an HLA-DR15-specific inhibitor, would effectively block HLA-DR15 presentation of the dominant epitope, attenuate the activation of autoreactive T cells, and limit disease. Using humanised HLA-DR15 transgenic mice, α3_135-145-specific, pro-inflammatory T cell recall responses were measured using IFN-γ and IL-17A ELISPOTs and by proliferation assay. To determine if PV-267 could limit disease, experimental autoimmune anti-GBM glomerulonephritis was induced in HLA-DR15 transgenic mice (on an Fcgr2b^-/- background), and functional and histological disease endpoints were measured. PV-267 effectively inhibited α3_135-145-specific immune responses and disease development. Mice treated prior to immunization with α3_135-145 had reduced α3_135-145-specific recall responses, and limited disease by albuminuria, histological glomerular injury, IgG deposition, and inflammatory cell infiltrates. PV-267 treatment commencing after the onset of active anti-α3(IV)NC1 autoimmunity attenuated functional and histological renal injury. When treatment was administered after disease was established, PV-267 limited the severity of histological injury. In conclusion, HLA-DR15 inhibition attenuates α3(IV)NC1-specific pro-inflammatory responses and could be used as an adjunct therapy for anti-GBM disease.

2017-10-02·Cell Cycle3区 · 生物学

Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212

3区 · 生物学

Article

作者: Kline, Christina Leah ; Nallaganchu, Bhaskara Rao ; Oster, Wolfgang ; Benes, Cyril H. ; Ralff, Marie D. ; Prabhu, Varun V. ; Zhou, Lanlan ; Stogniew, Martin ; Olson, Gary L. ; Wagner, Jessica ; Lev, Avital ; Allen, Joshua E. ; El-Deiry, Wafik S. ; Lulla, Amriti

Anti-cancer small molecule ONC201 upregulates the integrated stress response (ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene activation. ONC201 is under investigation in multiple clinical trials to treat patients with cancer. Given the unique imipridone core chemical structure of ONC201, we synthesized a series of analogs to identify additional compounds with distinct therapeutic properties. Several imipridones with a broad range of in vitro potencies were identified in an exploration of chemical derivatives. Based on in vitro potency in human cancer cell lines and lack of toxicity to normal human fibroblasts, imipridones ONC206 and ONC212 were prioritized for further study. Both analogs inhibited colony formation, and induced apoptosis and downstream signaling that involves the integrated stress response and Akt/ERK, similar to ONC201. Compared to ONC201, ONC206 demonstrated improved inhibition of cell migration while ONC212 exhibited rapid kinetics of activity. ONC212 was further tested in >1000 human cancer cell lines in vitro and evaluated for safety and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at nanomolar concentrations across solid tumors and hematological malignancies. Skin cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally administered ONC212 displayed potent anti-tumor effects in vivo, a broad therapeutic window and a favorable PK profile. ONC212 was efficacious in vivo in BRAF V600E melanoma models that are less sensitive to ONC201. Based on these findings, ONC212 warrants further development as a drug candidate. It is clear that therapeutic utility extends beyond ONC201 to include additional imipridones.

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