Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma affecting children and young adults. About 30% of patients develop therapy resistance therefore new precision medicine drugs are highly warranted. Multiple rounds of structure-activity optimization of Caffeic Acid Phenethyl Ester have resulted in CM14. CM14 causes upregulation of genes involved in oxidative stress response and downregulation of DNA replication genes leading to G2/M arrest and subsequent apoptosis induction. In accordance with this, an unbiased proteomics approach, confocal microscopy and molecular modeling showed that TUBGCP2, member of the centrosomal γ-TuRC complex, is a direct interaction partner of CM14. CM14 overcomes ALK inhibitor resistance in ALCL and is also active in T-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia. Interestingly, CM14 also induced cell death in docetaxel-resistant prostate cancer cells thus suggesting an unexpected role in solid cancers. Thus, we synthesized and thoroughly characterized a novel TUBGCP2 targeting drug that is active in ALCL but has also potential for other malignancies.

• MeSH
• apoptóza účinky léků   MeSH
• centrozom * účinky léků   metabolismus   MeSH
• chemorezistence účinky léků   MeSH
• fenethylalkohol * farmakologie   analogy a deriváty   chemie   MeSH
• kyseliny kávové * farmakologie   chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• protinádorové látky * farmakologie   chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• caffeic acid phenethyl ester MeSH Prohlížeč
• fenethylalkohol * MeSH
• kyseliny kávové * MeSH
• protinádorové látky * MeSH

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.

• Klíčová slova
• ALCL, PDX, brigatinib, crizotinib, tyrosine kinase inhibitors,
• MeSH
• anaplastická lymfomová kináza MeSH
• anaplastický velkobuněčný lymfom * farmakoterapie   patologie   MeSH
• dítě MeSH
• heterografty MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• krizotinib farmakologie   terapeutické užití   MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• nádory plic * farmakoterapie   MeSH
• nemalobuněčný karcinom plic * MeSH
• organofosforové sloučeniny farmakologie   terapeutické užití   MeSH
• tyrosinkinasové receptory terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anaplastická lymfomová kináza MeSH
• brigatinib MeSH Prohlížeč
• inhibitory proteinkinas MeSH
• krizotinib MeSH
• organofosforové sloučeniny MeSH
• tyrosinkinasové receptory MeSH

Non-Hodgkin lymphoma (NHL) is the third most common malignancy diagnosed in children. The vast majority of paediatric NHL are either Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma (LL). Multi-agent chemotherapy is used to treat all of these types of NHL, and survival is over 90% but the chemotherapy regimens are intensive, and outcomes are generally poor if relapse occurs. Therefore, targeted therapies are of interest as potential solutions to these problems. However, the major problem with all targeted agents is the development of resistance. Mechanisms of resistance are not well understood, but increased knowledge will facilitate optimal management strategies through improving our understanding of when to select each targeted agent, and when a combinatorial approach may be helpful. This review summarises currently available knowledge regarding resistance to targeted therapies used in paediatric anaplastic lymphoma kinase (ALK)-positive ALCL. Specifically, we outline where gaps in knowledge exist, and further investigation is required in order to find a solution to the clinical problem of drug resistance in ALCL.

• Klíčová slova
• anaplastic large cell lymphoma, chemotherapy, nucleophosmin1-anaplastic lymphoma kinase, paediatric cancer, resistance,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.

• MeSH
• anaplastický velkobuněčný lymfom farmakoterapie   genetika   metabolismus   patologie   MeSH
• antigen Ki-1 genetika   metabolismus   MeSH
• imunokonjugáty farmakologie   MeSH
• interleukin-15 farmakologie   MeSH
• interleukin-2 farmakologie   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• receptor interleukinu-2 - alfa-podjednotka genetika   imunologie   metabolismus   MeSH
• receptory interleukinu-2 genetika   imunologie   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• regulační oblasti nukleových kyselin MeSH
• represorové proteiny genetika   metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• transkripční faktory bZIP genetika   metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen Ki-1 MeSH
• BATF3 protein, human MeSH Prohlížeč
• IL2RA protein, human MeSH Prohlížeč
• imunokonjugáty MeSH
• interleukin-15 MeSH
• interleukin-2 MeSH
• receptor interleukinu-2 - alfa-podjednotka MeSH
• receptory interleukinu-2 MeSH
• represorové proteiny MeSH
• transkripční faktory bZIP MeSH