Abstract 1372: Towards novel strategies of targeting specific vulnerabilities of T-PLL cells
Authors: Sabine Puetzer, Emma Andersson, Alexandra Schrader, Lesley Varghese, M Hülsemann, Petra Mayer, Marc-Henri Stern, Sebastian Newrzela, L Frenzel, Satu Mustjoki, Marco Herling
Journal: Cancer Research (2017)

Abstract T-cell prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm usually presenting at an aggressive phase and a marked resistance to conventional cytostatics, i.e. alkylators. The monoclonal antibody alemtuzumab induces high response rates, but virtually all patients relapse and the mostly elderly individuals are often ineligible for allogeneic stem cell transplantation. Overall, the treatment options for T-PLL are scarce and its general prognosis with average survival times of &amp;lt;3 yrs. remains poor. In agreement with the pronounced amenability of T-cell tumors to intervention in the altered epigenetic code, recent reports also implicate a high potential of epigenetic targeting in T-PLL. In fact, profiling of anti-nucleoside sensitivities, including clinically used agents like fludarabine or nelarabine, revealed that the purine analog cladribine showed the highest T-PLL specific activity (LD50s: 0.16µM in T-PLL; 2.95µM in healthy-donor T-cells, 2.81µM in PBMC), potentially through its epigenetically active pyrimidine function. Fittingly, high-throughput genomic analysis of 95 T-PLL revealed alterations enriched in DNA repair genes and histone / DNA epigenetic modifiers. Extensive ex vivo drug screens (306 substances, 39 T-PLL) corroborated the genomic data and identified major clusters of T-PLL-active substances. The CDK inhibitor SNS-032 induced the highest T-PLL specific responses, followed by p53 activators, BCL2-family antagonists, and modulators of protein acetylation and chromatin accessibility, all surpassing the effects of JAK/STAT-inhibitors. The BCL2 inhibitor ABT199 (Venetoclax) profoundly affected T-PLL cell viability (LD50=6.9nM), although apoptosis was induced more efficiently in CLL cells (LD50=2.4nM). This slightly lower cytotoxicity in T-PLL might be explained by the more heterogeneous BCL2 expression in this disease than in CLL (flow-cytometry and gene expression arrays; 70 T-PLL). The best-performing substance of the set, SNS-032, selectively and profoundly induced apoptosis in T-PLL (LD50=0.19µM vs 0.47µM in normal T-cells vs 0.88µM in PBMC). Recognized as a CDK inhibitor, it antagonizes transcription via targeting CDK7 and -9. We identified associations of protein levels of the transcription factor MYC with the in vitro responses to SNS-032. Amplified cMYC is one of the genomic hallmarks of T-PLL and implicated in its aggressive phenotype. Hence it may be a target of SNS-032 or serve as a biomarker for SNS-032 sensitivity.In summary, we identified several substances with marked anti-leukemic activity in T-PLL. In vitro studies confirmed their potency and selectivity that could be aligned with identified protein and genomic-lesional target patterns. Follow-up studies of members of the major clusters of most T-PLL-active compounds including their best-informed combinations and pre-clinical in-vivo testing will guide in the design of promising clinical trials in T-PLL. Note: This abstract was not presented at the meeting. Citation Format: Sabine Puetzer, Emma Andersson, Alexandra Schrader, Lesley Varghese, M Hülsemann, Petra Mayer, Marc-Henri Stern, Sebastian Newrzela, L Frenzel, Satu Mustjoki, Marco Herling. Towards novel strategies of targeting specific vulnerabilities of T-PLL cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1372. doi:10.1158/1538-7445.AM2017-1372