Augmented efficacy of brentuximab vedotin combined with ruxolitinib and/or Navitoclax in a murine model of human Hodgkin's lymphoma.

Therapeutic Approaches

Abstract

Despite relative success of therapy for Hodgkin's lymphoma (HL), novel therapeutic agents are needed for patients with refractory or relapsed disease. Recently, anti-PD1 immunotherapy or treatment with the anti-CD30 toxin conjugate brentuximab vedotin (BV) have been associated with remissions; however, the median responses of complete responses (CRs) with the latter were only 6.7 mo. To obtain curative therapy, other effective agents, based on HL biology, would have to be given in combination with BV. Hodgkin's Reed-Sternberg (HRS) cells secrete cytokines including IL-6 and -13, leading to constitutive activation of JAK/STAT signaling. In the present study the JAK1/2 inhibitor ruxolitinib reduced phosphorylation of STAT3 and STAT6 and expression of c-Myc in the HL cell line HDLM-2. These changes were enhanced when, on the basis of a matrix screen of drug combinations, ruxolitinib was combined with the Bcl-2/Bcl-xL inhibitor Navitoclax. The combination augmented expression of Bik, Puma, and Bax, and attenuated Bcl-xL expression and the phosphorylation of Bad. The use of the two-agent combination of either ruxolitinib or Navitoclax with BV or the three-agent combination strongly activated Bax and increased activities of cytochrome c and caspase-9 and -3 that, in turn, led to cleavage of poly(ADP ribose) polymerase and Mcl-1. Either ruxolitinib combined with Navitoclax or BV alone prolonged survival but did not cure HDLM-2 tumor-bearing mice, whereas BV combined with ruxolitinib and/or with Navitoclax resulted in a sustained, complete elimination of the HDLM-2 HL. These studies provide scientific support for a clinical trial to evaluate BV combined with ruxolitinib in select patients with HL.

Authors

Ju, Wei; Zhang, Meili; Wilson, Kelli; Petrus, Michael N; Bamford, Richard N; Zhang, Xiaohu; Guha, Rajarshi; Ferrer-Alegre, Marc; Thomas, Craig; Waldmann, Thomas A;

Keywords

  • Aniline Compounds/ pharmacology
  • Aniline Compounds/ therapeutic use
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols/ pharmacology
  • Antineoplastic Combined Chemotherapy Protocols/ therapeutic use
  • Apoptosis/ drug effects
  • Blotting, Western
  • Caspase 3/ metabolism
  • Caspase 7/ metabolism
  • Cell Line, Tumor
  • Cell Proliferation/ drug effects
  • Disease Models, Animal
  • Disease Progression
  • Drug Evaluation, Preclinical
  • Enzyme Activation/ drug effects
  • Gene Dosage
  • Hodgkin Disease/ drug therapy
  • Hodgkin Disease/ enzymology
  • Hodgkin Disease/ pathology
  • Humans
  • Immunoconjugates/ pharmacology
  • Immunoconjugates/ therapeutic use
  • Janus Kinase 2/ genetics
  • Mice
  • Mitochondria/ drug effects
  • Mitochondria/ metabolism
  • Phosphorylation/ drug effects
  • Pyrazoles/ pharmacology
  • Pyrazoles/ therapeutic use
  • STAT Transcription Factors/ metabolism
  • Signal Transduction/ drug effects
  • Sulfonamides/ pharmacology
  • Sulfonamides/ therapeutic use
  • Treatment Outcome
  • bcl-X Protein/ metabolism

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