Austrian research team identifies new therapeutic target for leukemic cutaneous T-cell lymphoma

Leukemic cutaneous T-cell lymphoma (L-CTCL) is a rare type of skin cancer that presents varied clinical features and symptoms. In a recently published study by the University of Veterinary Medicine Vienna and the Medical Universities of Vienna and Graz, the researchers managed to integrate the genomic data from affected patients with pharmacologic studies. This innovative research approach has led to the identification of STAT3/5 and PAK kinase as potential new therapeutic targets.

Despite numerous genomic sequencing efforts, no characteristic driver mutations for L-CTCL have been identified to date. Chromosomal losses and gains, however, are known to be frequent and dominant in L-CTCL. To gain new insights into the causes of the disease and to identify possible new targets for therapies, the research team took a new approach: For their study, published in EMBO Molecular Medicine, the research team integrated genomic analyses with pharmacologic interference studies to identify key mutations leading to the disease and so explore new therapeutic approaches.

PAK inhibitor FRAx597 inhibits tumour growth and disease dissemination
-In 74% of the L-CTCL patients studied, we detected increased copy numbers of loci containing STAT3/5 oncogenes, which correlated with an increased T-cell count in the blood. With specific inhibition of STAT3/5 and PAK kinase using multikinase blockers, we were able to prevent L-CTCL cell growth in vitro and ex vivo. We were particularly pleased that we were also able to prevent tumour growth in L-CTCL cells from patients whose genome showed STAT3/5 gains,- explains first author Helena Sorger from the Department of Functional Cancer Genomics at Vetmeduni Vienna and the Department of Pediatric and Adolescent Surgery at MedUni Vienna. The PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumour growth and disease dissemination in mouse experiments. -We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic approach that needs to be further explored in L-CTCL,- Sorger said of the study’s promising results, which point the way towards new treatment options.

Rare form of skin cancer with varied clinical features
Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of non-Hodgkin lymphomas characterized by the infiltration and expansion of neoplastic mature T-cells, primarily in the skin. In L-CTCL, the T cell lymphocytes, which in a healthy person are an important part of the body’s immune system, develop abnormalities that make them attack the skin.

Publication: EMBO Molecular Medinine
Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma
Helena Sorger, Saptaswa Dey, Pablo Augusto Vieyra-Garcia, Daniel Pölöske, Andrea R Teufelberger, Elvin D de Araujo, Abootaleb Sedighi, Ricarda Graf, Benjamin Spiegl, Isaac Lazzeri,Till Braun, Ines Garces de los Fayos Alonso, Michaela Schlederer, Gerald Timelthaler, Petra Kodajova, Christine Pirker, Marta Surbek, Michael Machtinger, Thomas Graier, Isabella Perchthaler, Yi Pan, Regina Fink-Puches, Lorenzo Cerroni, Jennifer Ober, Moritz Otte, Jana D Albrecht, Gary Tin, Ayah Abdeldayem, Pimyupa Manaswiyoungkul, Olasunkanmi O Olaoye, Martin L Metzelder, Anna Orlova, Walter Berger, Marion Wobser, Jan P Nicolay, Fiona André, Van Anh Nguyen, Heidi A Neubauer, Roman Fleck, Olaf Merkel, Marco Herling, Ellen Heitzer, Patrick T Gunning, Lukas Kenner, Richard Moriggl, Peter Wolf­emmm.202115200­full/10.15252/­emmm.202115200