Ontogeny and oncogenic potential of genetic alterations in peripheral T-cell lymphomas
Final Report Abstract
My postdoctoral fellowship in the laboratory of Prof. David M. Weinstock at the Dana-Farber Cancer Institute in Boston, USA, was an incredible experience that profoundly improved my skills in the field of translational research in T-cell lymphomas and my personality as a clinician scientist! Prof. Weinstock provided an environment that allowed to address multiple different aspects in translational research, from basic science and model generation to clinical trials and correlative science. In the context of a Specialized Center of Research, funded by the Leukemia and Lymphoma Society, he successfully brought together clinicians, pathologist and basic scientist to collaboratively improve our understanding of these diseases and develop novel therapeutic strategies. In ongoing collaborations he strongly supports my re-integration as a clinician scientist at the University of Göttingen. The goal of this fellowship was to improve the biologic understanding of crucial mechanisms driving T-cell lymphomagenesis and identify targets for novel therapeutic strategies. The initial proposal entitled “Ontogeny of peripheral T-cell lymphomas” focused on the characterization of the timing and cellular context of pathogenetically relevant mutations during T-cell lymphomagenesis in order to identify potential new therapeutic targets. Sequencing of T-cell lymphoma samples, though, revealed a very heterogeneous pattern of mutations. Sequencing of the corresponding stem cell products identified TET2 mutations in hematopoietic progenitors of patients with AITL at different maturation stages. However, regarding mutations in additional genes, the sample size of the project did not allow to identify new candidates of significant recurrence. In an ongoing project, stem cell products from 38 additional patients with T-cell lymphomas are being sequenced. While sequencing efforts were ongoing, I focused on the utilizing pre-clinical models of T-cell lymphomas to address potential new targets for T-cell lymphomas. Importantly, the Weinstock lab established >300 new patient-derived xenograft (PDX) models of leukemias and lymphomas (Townsend et al., Cancer Cell 2016; publically available at www.PRoXe.org), including T-cell lymphomas. We performed a comprehensive characterization of T-cell lymphoma PDX models and previously established cell lines. As outlined above, we successfully utilized these models to assess the phosphoinositide 3-kinase (PI3K) pathway as a therapeutic target in PTCL, leading to a rational combination strategy that now undergoes clinical testing. Furthermore, we identified re-activation of the P53 pathway and targeting the mitochondrial apoptosis pathway as new biomarker-driven therapeutic strategies in T-cell lymphomas. At the Department of Hematology and Oncology at the University Medical Center of Göttingen I will focus on basic science to further elucidate the biology of T-cell lymphomas and the development of therapeutic strategies, testable in clinical trials.
Publications
- Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone. Clin Cancer Res. 2016 Jan 15;22(2):395-404
Koch R, Aung T, Vogel D, Chapuy B, Wenzel D, Becker S, Sinzig U, Venkataramani V, von Mach T, Jacob R, Truemper L, Wulf GG
(See online at https://doi.org/10.1158/1078-0432.CCR-15-0577) - The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice. Cancer Cell. 2016 Jul 11;30(1):183
Townsend EC, Murakami MA, Christodoulou A, Christie AL, Köster J, DeSouza TA, Morgan EA, Kallgren SP, Liu H, Wu SC, Plana O, Monteäro J, Stevenson KE, Rao P, Vadhi R, Andreeff M, Armand P, Ballen KK, Barzaghi-Rinaudo P, Cahill S, Clark RA, Cooke VG, Davids MS, DeAngelo DJ, Dorfman DM, Eaton H, Ebert BL, Etchin J, Firestone B, Fisher DC, Freedman AS, Galinsky IA, Gao H, Garcia JS, Garnache-Ottou F, Graubert TA, Gutierrez A, Halilovic E, Harris MH, Herbert ZT, Horwitz SM, Inghirami G, Intlekofer AM, Ito M, Izraeli S, Jacobsen ED, Jacobson CA, Jeay S, Jeremias I, Kelliher MA, Koch R, ... Weinstock DM
(See online at https://doi.org/10.1016/j.ccell.2016.03.008) - Activity of the PI3K-δ,γ inhibitor duvelisib in a phase I trial and preclinical models of T-cell lymphoma. Blood. 2017 Dec 12
Horwitz SM, Koch R, Porcu P, Oki Y, Moskowitz A, Perez M, Myskowski P, Officer A, Jaffe JD, Morrow SN, Allen K, Douglas M, Stern H, Sweeney J, Kelly P, Kelly V, Aster JC, Weaver D, Foss FM, Weinstock DM
(See online at https://doi.org/10.1182/blood-2017-08-802470) - Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models. Nature Communications, 2018
Ng SY, Yoshida N, Christie AL, Ghandi M, Dharia NV, Dempster J, Murakami M, Shigemori K, Morrow SN, Van Scoyk A, Cordero NA, Stevenson KE, Puligandla M, Haas B, Lo C, Meyers R, Gao G, Cherniack A, Louissaint JR A, Nardi V, Thorner AR, Long H, Qiu X, Morgan EA, Dorfman DM, Fiore D, Jang J, Epstein AL, Dogan A, Zhang Y, Horwitz SM, Jacobsen ED, Santiago A, Ren JG, Guerlavais V, Annis DA, Aivado M, Tsherniak A, Root D, Vazquez F, Hahn WC, Inghirami G, Aster JC, Weinstock DM & Koch R
(See online at https://doi.org/10.1038/s41467-018-04356-9)
