23.09.2022: 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 University of Veterinary Medicine Vienna and the Medical University of Vienna has now identified a new biomarker and effective therapeutic approach with the protein PDGFRβ 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 PDGFRβ.
Protein PDGFRβ accelerates tumor growth
A recent international study led by Dr. Sabine Lagger at the Laboratory Animal Pathology, Vetmeduni and Prof. Lukas Kenner at the Laboratory Animal Pathology, Vetmeduni and Clinical Institute of Pathology of MedUni Vienna has now identified a new biomarker and therapeutic approach with the protein PDGFRβ. In this study, Garces de los Fayos Alonso et al. describe that the STAT3/5 signaling pathway is downstream of the PDGFRβ protein and is partly responsible for these tumors becoming more aggressive. Lukas Kenner summarizes the conclusions, "We have found PDGFRβ as a new biomarker and consider PDGFRβ-STAT3/5 signaling to be the central factor in aggressive ALCL tumors. Furthermore, we assume that inhibition of PDGFRβ and/or STAT3/5 will massively improve survival of patients with ALCL."
Efficacy of drug combinations
As part of her dissertation, Ines Garces not only succeeded in identifying the role of PDGFRβ 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 PDGFRβ-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.
The article „PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma“ by I. Garces de los Fayos Alonso, L. Zujo, I. Wiest, P. Kodajova, G. Timelthaler, S. Edtmayer, M. Zrimšek, 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 and L. Kenner was published in „Molecular Cancer“.