15.12.2022: Leukemic cutaneous T-cell lymphoma (L-CTCL) is a rare type of 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,” explain first authors Helena Sorger from the Department of Functional Cancer Genomics at Vetmeduni and the Department of Pediatric and Adolescent Surgery at MedUni Vienna and Saptaswa Dey  from theDepartment of Dermatology and Venereology at Med Uni Graz.

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 and Dey 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 and blood. 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. This results, among other things, in an increased susceptibility to infections and a tendency to sepsis.

The article “Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma” by Helena Sorger, Saptaswa Dey, Peter Wolf, Richard Moriggl, Patrick Gunning, Lukas Kenner et al. was published in EMBO Molecular Medicine.

Scientific article