Anaplastic large cell lymphoma (ALCL) is an aggressive blood cancer that mainly affects children and adolescents, but it can also affect adults. A recent international study led by scientists from the Medical University Vienna and the Veterinary Medicine Vienna has now identified a new biomarker and effective therapeutic approach with the protein PDGFRÎ² and its downstream signaling pathway STAT3/5. According to the researchers, the inhibition of this axis promises a therapy with significantly improved prospects of success.
Anaplastic large cell lymphoma (ALCL) is a very aggressive lymph node cancer that originates from immune T cells and is often caused by the protein NPM-ALK. It is a fusion protein of nucleophosmin (NPM) and anaplastic lymphoma kinase (ALK). Targeting this fusion protein is highly effective, but often leads to relapse. The two transcription factors cJUN and JUNb play a central role in the development of ALCL. They are downstream of the protein NPM-ALK and regulate the protein PDGFRÎ².
Protein PDGFRÎ² accelerates tumor growth
A recent international study led by Sabine Lagger (Vetmeduni Vienna) and Lukas Kenner (MedUni Vienna and Vetmeduni Vienna) has now identified a new biomarker and therapeutic approach with the protein PDGFRÎ². In this study, Ines Garces de los Fayos Alonso and others describe that the STAT3/5 signaling pathway is downstream of the PDGFRÎ² protein and is partly responsible for these tumors becoming more aggressive. Lukas Kenner summarizes the conclusions: "We have found PDGFRÎ² as a new biomarker and consider PDGFRÎ²-STAT3/5 signaling to be the central factor in aggressive ALCL tumors. Furthermore, we assume that inhibition of PDGFRÎ² and/or STAT3/5 will massively improve survival of patients with ALCL."
Efficacy of drug combinations
As part of her dissertation, Ines Garces de los Fayos Alonso (Clinical Institute of Pathology of MedUni Vienna) not only succeeded in identifying the role of PDGFRÎ² in tumor development, but also demonstrated that inhibition of the entire pathway is an effective therapeutic strategy for relapsed patients. The results in the mouse model are promising for people suffering from PDGFRÎ²-driven ALCL. Sabine Lagger says, "This signaling pathway acts as a double-edged sword, giving malignant cells a selective advantage that increases their carcinogenic potential, while also providing an alternative pathway for pharmacological inhibition." According to the scientists, further studies are now needed to learn more about additional kinases and their underlying molecular mechanisms so that better drug combinations can be developed to prevent tumor recurrence.
Publication: Molecular Cancer
PDGFRÎ² promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma I.Garces de los Fayos Alonso, L. Zujo, I. Wiest, P. Kodajova, G. Timelthaler, S. Edtmayer, M. Zrim¨ek, S. Kollmann, C. Giordano, M. Kothmayer, H. A. Neubauer, S. Dey, M. Schlederer, B. S. Schmalzbauer, T. Limberger, C. Probst, O. Pusch, S. Högler, S. Tangermann, O. Merkel, A. I. Schiefer, C. Kornauth, N. Prutsch, M. Zimmerman, B. Abraham, J. Anagnostopoulos, L. Quintanilla-Martinez, S. Mathas, P. Wolf, D. Stoiber, P. B. Staber, G. Egger, W. Klapper, W. Woessmann, T. A. Look, P. Gunning, S. D. Turner, R. Moriggl, S. Lagger & L. Kenner
Doi: https://doi.org/10.1186/s12943’022 -01640-7