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1.
NPJ Precis Oncol ; 7(1): 109, 2023 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-37884744

RESUMO

Analysis of selected cancer genes has become an important tool in precision oncology but cannot fully capture the molecular features and, most importantly, vulnerabilities of individual tumors. Observational and interventional studies have shown that decision-making based on comprehensive molecular characterization adds significant clinical value. However, the complexity and heterogeneity of the resulting data are major challenges for disciplines involved in interpretation and recommendations for individualized care, and limited information exists on how to approach multilayered tumor profiles in clinical routine. We report our experience with the practical use of data from whole-genome or exome and RNA sequencing and DNA methylation profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program of the National Center for Tumor Diseases (NCT) Heidelberg and Dresden and the German Cancer Research Center (DKFZ). We cover all relevant steps of an end-to-end precision oncology workflow, from sample collection, molecular analysis, and variant prioritization to assigning treatment recommendations and discussion in the molecular tumor board. To provide insight into our approach to multidimensional tumor profiles and guidance on interpreting their biological impact and diagnostic and therapeutic implications, we present case studies from the NCT/DKFZ molecular tumor board that illustrate our daily practice. This manual is intended to be useful for physicians, biologists, and bioinformaticians involved in the clinical interpretation of genome-wide molecular information.

2.
Cancer Lett ; 405: 63-72, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28716527

RESUMO

Recently, copy number gains and increased expression levels of cIAP1 and cIAP2 have been reported in B-cell non-Hodgkin lymphomas (NHL). Therefore, we investigated the therapeutic potential of the Smac mimetic BV6 that antagonizes cIAP1/2 and XIAP. Here, we discover that subtoxic concentrations of BV6 prime B-cell NHL cells to proteasome inhibitor Bortezomib-induced cell death. Synergistic induction of cell death by BV6 and Bortezomib is confirmed by calculation of combination index in different cell lines, emphasizing the broader relevance of this combination. Interestingly, addition of the caspase inhibitor zVAD.fmk provides no or only partial protection from BV6/Bortezomib-stimulated cell death. Consistently, BV6/Bortezomib co-treatment alone or in combination with zVAD.fmk increases phosphorylation of MLKL, a typical marker of necroptosis. Importantly, genetic silencing of key components of necroptosis signaling such as MLKL or RIP3 significantly protects DG-75 cells from BV6/Bortezomib-induced cell death in the presence and even the absence of zVAD.fmk. Similarly, pharmacological inhibitors of MLKL (i.e. NSA), RIP3 (i.e. GSK'872, Dabrafenib) or RIP1 (i.e. Necrostatin-1s) significantly rescue DG-75 cells from BV6/Bortezomib-induced cell death irrespective of the presence of zVAD.fmk. In addition, NSA or Nec-1s act in concert with zVAD.fmk to reduce BV6/Bortezomib-induced cell death in U-2932 cells. Together, these findings demonstrate that BV6 and Bortezomib synergize to induce cell death in B-cell NHL cells. BV6/Bortezomib co-treatment primarily triggers necroptosis or, alternatively, engages both apoptotic and necroptotic cell death. The discovery of this synergistic combination that is effective even when apoptosis is blocked has important implications for the development of new treatment strategies for B-cell NHL.


Assuntos
Antineoplásicos/farmacologia , Bortezomib/farmacologia , Morte Celular/efeitos dos fármacos , Linfoma não Hodgkin/tratamento farmacológico , Oligopeptídeos/farmacologia , Apoptose/efeitos dos fármacos , Biomimética , Linhagem Celular Tumoral , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos
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