Anaplastic Large Cell Lymphoma (ALCL) is a Non-Hodgkin lymphoma found in children and young adults with poor survival rates. ALCLs frequently carry a genomic lesion (chromosomal translocation) that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). Despite our knowledge about the molecular trigger for the lymphoma, the downstream events which promote tumour growth and development remained elusive. Cancer is often characterised by the collaboration of aberrantly activated signalling pathways, which establish a tumour specific gene expression programme. This results in a network of signal mediators to cooperatively sustain and promote tumour growth. This fact makes cancer often difficult to treat, as targeting a single molecule with therapeutic agents is frequently compensated by other players in the network. Lukas Kenner stresses, “We were convinced elucidating the key molecular events required for NPM-ALK triggered lymphoma growth would provide hints to better treatment options of the disease.” Clinically ALCL is difficult to control, as even targeted therapy against NPM-ALK with Crizotinib frequently results in a life threatening relapse after initial tumour regression. This indicates ALCL at the time of treatment relies already on secondary signals, which are sufficient to maintain tumour growth.
The researchers around Kenner analysed a murine tumour model expressing the fusion-protein NPM-ALK, which mimics the oncogenic lesion frequently observed in ALCL patients. They investigated a plethora of candidates downstream of the initial lesion for their contribution to the molecular signalling network induced by forced NPM-ALK expression. The researchers could pinpoint a specific gene product, the PDGFR as a central signal integrator. PDGFR has been implicated in several tumours, but for Lymphomas this finding was new. Therefore Kenner attempted to interfere with PDGFR signalling with Imatinib, an established compound used for the treatment of other tumours. Imatinib could greatly enhance the efficacy of Crizotinib as it prolonged survival of NPM-ALK transgenic mice and in transplanted NPM-ALK tumors. Kenner stresses: “It was crucial to analyse the tumors in a tailored murine model of ALCL, as meaningful interference studies are impossible to be performed in vitro or in patients.”
Strikingly, these results observed in the murine tumour model could be directly translated into clinical application. Screening a number of patient samples applying the Histoquant technology by TissueGnostics Ltd. the team observed a strong expression and activation of PDGFR in more than 90 % of 250 ALCL tumors. This prompted the team to explore PDGFR inhibition with the compound Imatinib in an ALCL patient. They obtained ethical approval and informed consent to treat a late stage patient with refractory NPM-ALK-positive ALCL with Imatinib. This resulted in complete and sustained remission within 10 days of treatment and the patient is still feeling fine 19 months on. Lukas Kenner: “It is still early days, but for now this saved his life. I am impressed by his recovery, the patient has been back at work for months now. Without testing the concept of the PDGFR inhibition in animals we had neither had the scientific confidence nor the ethical grounds to proceed with treating this patient.” These results identify PDGFR inhibition as a potentially highly effective therapy to cure ALCL.
The cited report in "Nature Medicine" describes the identification of PDGFR as crucial signalling component in NPM-ALK lymphomas, and the successful treatment of an ALCL patient without further treatment option with a PDGFR inhibitor. The team is currently engaged in research to analyse the strong therapeutic success but also efforts to corroborate the initial findings with a multi-centric clinical trial are under way. Lukas Kenner: “It was particularly gratifying to see our analysis could inform therapy and I hope many patients will benefit from our research in animal models in the near future.”
We are grateful for the public interest our research findings sparked. In particular we are proud that our research raises a perspective for some lymphoma patients in the foreseeable future. This is the greatest benefit our research can have. If you are interested to learn about further details about the implications of our research we would like to refer you to the information our collaborators from the Medical University Vienna made available recently via their website. We would like to stress that the treatment, which saved the life of one ALCL patient, remains to be confirmed in its effectiveness in a properly controlled clinical study.