Panobinostat (LBH589) in combination with the β-catenin inhibitor Tegavivint (BC2059) exerts significant anti-myeloma activity both in vitro and in vivo

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Abstract

Introduction: Panobinostat (LBH589) is approved for the treatment of relapsed myeloma (MM). The Wnt canonical pathway and its key player, β-catenin are dysregulated in advanced MM supporting the evaluation of β-catenin inhibition as a potential therapy. We evaluated the anti-MM effect of Tegavivint (BC2059) in combination with LBH589 in vitro and in vivo. Results and Methods: In vitro combination of low doses (BC2059≤100nM; LBH589≤10nM) for 48h was synergistic against both OCI-My1 and U266 MM cells, with combination indices (CI) ranging from 0.569 to 0.883 (CI<1: synergism). Similarly, the combination demonstrated synergistic killing of primary MM tumour cells in a validated autologous co-culture assay with synergism quotients (SQ) ranging from 1.2 to 2 (SQ>1: synergism). The combination rapidly (<24h) decreased the expression of downstream β-catenin targets c-myc, pan-myc, cyclinD1 and cyclinD2 as shown by immunoblotting. Furthermore, by 20h, the combination decreased both oxidative phosphorylation and aerobic glycolysis as measured by oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), respectively (Seahorse XFe96 analyser). Basal, maximal and ATP coupled OCR was also significantly reduced by the combination when compared to vehicle (for OCIMy1 from 203.93 to 56.20, from 105.81 to 33.29  and from 156.29 to 34.67 pmol/min/50K cells OCR respectively). Similarly, glycolytic activity was also inhibited by the combination reducing both basal glycolysis and glycolytic capacity (from 48.88 to 9.77 and from 61.68 to 8.58 mpH/min/50K cells ECAR, respectively for OCI-My1). In vivo, BC2059 combined with LBH589 was superior to either single drug treatment in a murine xenograft of U266- luciferase cells. Disease burden was reduced in the combination arm compared to single drug and vehicle arms as early as day 14 after inoculation (p=0.02), the difference increasing through until the last day of bioluminescence imaging (day 49, p<0.001) and translated into significantly prolonged OS for the combination (p=0.006, Mantel-Cox test). Potential on-target toxicities with BC2059 are a concern as the Wnt canonical pathway is essential for stem cell maintenance in several organs and has a role in bone homeostasis, but the combination did not result in cytopenias nor body weight loss,implying maintenance of normal haematological and gastrointestinal function. After euthanasia, µCT demonstrated that neither BC2059 nor the combination negatively affected bone morphometric indices (bone volume fraction, trabecular thickness, connectivity density). Likewise, osteoblastic activity as measured by serum osteocalcin was unaffected, whereas osteoclastic activity (as indicated by serum CTX1) was reduced when compared to healthy mice (p=0.008 and p=0.013, respectively). Conclusion Panobinostat combined with Tegavivint may be an effective therapeutic modality for MM patients with advanced/refractory disease and warrants further evaluation. 
Original languageEnglish
Pagese137-e137
Number of pages1
DOIs
Publication statusPublished - 1 Oct 2019
EventInternational Myeloma Workshop 2019 - Hynes Convention Center, Boston, United States of America
Duration: 12 Sep 201915 Sep 2019
Conference number: 17th
http://imw2019boston.org/index.php/program (Conference Program)

Workshop

WorkshopInternational Myeloma Workshop 2019
Abbreviated titleIMW
CountryUnited States of America
CityBoston
Period12/09/1915/09/19
Internet address

Keywords

  • Myeloma,
  • treatment
  • HDACinhibitors
  • Wnt canonical pathway inhibitor
  • synergism
  • metabolosm

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