Augmented efficacy of brentuximab vedotin combined with ruxolitinib and/or Navitoclax in a murine model of human Hodgkin's Lymphoma. Jun, W., Zhang, M., Wilson, K., Petrus, M., Bamford, R., Zhang, X., Guha, R., Ferrer, M., Thomas, C., & Waldmann, T. Proc.~Nat.~Acad.~Sci., in press.
abstract   bibtex   
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 CRs with the latter were only 6.7 months. 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 IL-13 leading to constitutive activation of JAK/STAT signaling, therefore inhibition of JAK/STAT signaling could be a promising therapeutic target. In the present study the JAK1/2 inhibitor, ruxolitinib, reduced phosphorylation of STAT3 and STAT6, and expression of c-Myc in the HDLM-2 HL cell line. 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, 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, caspase-9 and caspase-3 that in turn led to cleavage of PARP 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.
@article{Jun:2015vn,
	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 CRs with the latter were only 6.7 months.  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 IL-13 leading to constitutive activation of JAK/STAT signaling, therefore inhibition of JAK/STAT signaling could be a promising therapeutic target.  
     In the present study the JAK1/2 inhibitor, ruxolitinib, reduced phosphorylation of STAT3 and STAT6, and expression of c-Myc in the HDLM-2 HL cell line. 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, 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, caspase-9 and caspase-3 that in turn led to cleavage of PARP 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.
},
	Author = {Jun, W. and Zhang, M. and Wilson, K. and Petrus, M.N. and Bamford, R. and Zhang, X. and Guha, R. and Ferrer, M. and Thomas, C. and Waldmann, T.A.},
	Date-Added = {2015-10-16 16:44:30 +0000},
	Date-Modified = {2015-12-31 19:38:24 +0000},
	Journal = {Proc.~Nat.~Acad.~Sci.},
	Title = {Augmented efficacy of brentuximab vedotin combined with ruxolitinib and/or Navitoclax in a murine model of human Hodgkin's Lymphoma},
	Year = {in press}}
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