D C DC. Phillips, Y Y. Xiao, L T LT. Lam, E E. Litvinovich, L L. Roberts-Rapp, A J AJ. Souers, J D JD. Leverson.
Blood cancer journal
2015 Nov; (5):e368
As a population, non-Hodgkin's lymphoma (NHL) cell lines positive for the t(14;18) translocation and/or possessing elevated BCL2 copy number (CN; BCL2(High)) are exquisitely sensitive to navitoclax or the B-cell lymphoma protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some BCL2(High) cell lines remain resistant to either agent. Here we show that the MCL-1-specific inhibitor A-1210477 sensitizes these cell lines to navitoclax. Chemical segregation of this synergy with the BCL-2-selective inhibitor venetoclax or BCL-XL-selective inhibitor A-1155463 indicated that MCL-1 and BCL-2 are the two key anti-apoptotic targets for sensitization. Similarly, the CDK inhibitor flavopiridol downregulated MCL-1 expression and synergized with venetoclax in BCL2(High) NHL cell lines to a similar extent as A-1210477. A-1210477 also synergized with navitoclax in the majority of BCL2(Low) NHL cell lines. However, chemical segregation with venetoclax or A-1155463 revealed that synergy was driven by BCL-XL inhibition in this population. Collectively these data emphasize that BCL2 status is predictive of venetoclax potency in NHL not only as a single agent, but also in the adjuvant setting with anti-tumorigenic agents that inhibit MCL-1 function. These studies also potentially identify a patient population (BCL2(Low)) that could benefit from BCL-XL (navitoclax)-driven combination therapy.
Regula R. Burkhard, Govind G. Bhagat, Sergio B SB. Cogliatti, Davide D. Rossi, Gianluca G. Gaidano, Laura L. Pasqualucci, Urban U. Novak.
2015 Mar; (33):23-30 1
BCL2 is a target of somatic hypermutation in t(14;18) positive and also in a small fraction of t(14;18) negative diffuse large B-cell lymphoma (DLBCL), suggesting an aberrant role of somatic hypermutation (ASHM). To elucidate the prevalence of BCL2 mutations in lymphomas other than DLBCL, we Sanger-sequenced the hypermutable region of the BCL2 gene in a panel of 69 mature B-cell lymphomas, including Richter's syndrome DLBCL, marginal-zone lymphomas, post-transplant lymphoproliferative disorders, HIV-associated and common-variable immunodeficiency-associated DLBCL, all known to harbour ASHM-dependent mutations in other genes, as well as 16 t(14,18) negative and 21 t(14;18) positive follicular lymphomas (FLs). We also investigated the pattern of BCL2 mutations in longitudinal samples from 10 FL patients relapsing to FL or transforming to DLBCL (tFL). By direct sequencing, we found clonally represented BCL2 mutations in 2/16 (13%) of t(14;18) negative FLs, 2/16 (13%) HIV-DLBCLs, 1/9 (11%) of Richter's syndrome DLBCL, 1/17 (6%) of post-transplant lymphoproliferative disorders and 1/2 (50%) common-variable immunodeficiency-associated DLBCL. The proportion of mutated cases was significantly lower than in FLs carrying the t(14;18) translocation (15/21, 71%). However, the absence of t(14;18) by FISH or PCR and the molecular features of the mutations strongly suggest that BCL2 represents an additional target of ASHM in these entities. Analysis of the BCL2 mutation pattern in clonally related FL/FL and FL/tFL samples revealed two distinct scenarios of genomic evolution: (i) direct evolution from the antecedent FL clone, with few novel clonal mutations acquired by the tFL major clone, and (ii) evolution from a common mutated long-lived progenitor cell, which subsequently acquired distinct mutations in the FL and in the relapsed or transformed counterpart.
Sylvia S. Herter, Frank F. Herting, Olaf O. Mundigl, Inja I. Waldhauer, Tina T. Weinzierl, Tanja T. Fauti, Gunter G. Muth, Doris D. Ziegler-Landesberger, Erwin E. Van Puijenbroek, Sabine S. Lang, Minh Ngoc MN. Duong, Lina L. Reslan, Christian A CA. Gerdes, Thomas T. Friess, Ute U. Baer, Helmut H. Burtscher, Michael M. Weidner, Charles C. Dumontet, Pablo P. Umana, Gerhard G. Niederfellner, Marina M. Bacac, Christian C. Klein.
Molecular cancer therapeutics
2013 Oct; (12):2031-42 10
We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved type I CD20 antibodies. The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and internalization. The models used for the comparison of their activity in vivo were SU-DHL4 and RL xenografts. GA101 was found to be superior to rituximab and ofatumumab in the induction of direct cell death (independent of mechanical manipulation required for cell aggregate disruption formed by antibody treatment), whereas it was 10 to 1,000 times less potent in mediating CDC. GA101 showed superior activity to rituximab and ofatumumab in ADCC and whole-blood B-cell depletion assays, and was comparable with these two in ADCP. GA101 also showed slower internalization rate upon binding to CD20 than rituximab and ofatumumab. In vivo, GA101 induced a strong antitumor effect, including complete tumor remission in the SU-DHL4 model and overall superior efficacy compared with both rituximab and ofatumumab. When rituximab-pretreated animals were used, second-line treatment with GA101 was still able to control tumor progression, whereas tumors escaped rituximab treatment. Taken together, the preclinical data show that the glyoengineered type II CD20 antibody GA101 is differentiated from the two approved type I CD20 antibodies rituximab and ofatumumab by its overall preclinical activity, further supporting its clinical investigation.
Andrew J AJ. Souers, Joel D JD. Leverson, Erwin R ER. Boghaert, Scott L SL. Ackler, Nathaniel D ND. Catron, Jun J. Chen, Brian D BD. Dayton, Hong H. Ding, Sari H SH. Enschede, Wayne J WJ. Fairbrother, David C S DC. Huang, Sarah G SG. Hymowitz, Sha S. Jin, Seong Lin SL. Khaw, Peter J PJ. Kovar, Lloyd T LT. Lam, Jackie J. Lee, Heather L HL. Maecker, Kennan C KC. Marsh, Kylie D KD. Mason, Michael J MJ. Mitten, Paul M PM. Nimmer, Anatol A. Oleksijew, Chang H CH. Park, Cheol-Min CM. Park, Darren C DC. Phillips, Andrew W AW. Roberts, Deepak D. Sampath, John F JF. Seymour, Morey L ML. Smith, Gerard M GM. Sullivan, Stephen K SK. Tahir, Chris C. Tse, Michael D MD. Wendt, Yu Y. Xiao, John C JC. Xue, Haichao H. Zhang, Rod A RA. Humerickhouse, Saul H SH. Rosenberg, Steven W SW. Elmore.
2013 Feb; (19):202-8 2
Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.