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Tackling high-risk leukemia: Austrian Science Fund FWF promotes precision oncology at St. Anna CCRI


Giulio Superti-Furga (© Klaus Pichler), Kaan Boztug, Michael Dworzak (Harald Eisenberger)

The innovative "ExTrAct AML" project, funded by the Austrian Science Fund FWF, goes beyond established frontiers to investigate acute myeloid leukemia (AML) in children and adolescents. Individual patient profiles should provide early information on the causes of disease progression or treatment resistance – and how to take countermeasures in time. In contrast to previous approaches, these profiles not only include comprehensive (epi)genetic signatures of the leukemia cells, but also their dysfunctional signaling pathways and sensitivity to more than 100 drugs – determined by a new and particularly precise method, that examines the effect of the drugs on cancer cells (pharmacoscopy). The highly endowed FWF grant goes to St. Anna Children's Cancer Research Institute (St. Anna CCRI) and its project partner, the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences.

AML is one of the most serious malignancies in children and adolescents. Despite intensive therapy, this type of leukemia still has a fatal course in about 25% of the patients and the reasons for disease relapses and treatment resistance are so far only partially understood. This is now set to change, thanks to a grant in the amount of € 585,000 from the FWF Clinical Research Program for the project Linking ex-vivo chemosensitivity, treatment and pathway activations for a deeper understanding of pediatric AML (ExTrAct-AML).

Scan for key signaling pathways

A team led by Univ.-Prof. Kaan Boztug, MD, Project Leader and Scientific Director of St. Anna CCRI, and Univ.-Prof. Giulio Superti-Furga, PhD, Scientific Director at CeMM, as well as Assoc.-Prof. Michael Dworzak, MD, Principal Investigator at St. Anna CCRI, aims to employ machine learning to create individual risk profiles of patients in order to ultimately provide each child with tailored treatment. Until now, personalized treatment approaches have mostly relied on individual genetic alterations of cancer cells as targets, which actually benefits only a few patients. Kaan Boztug and colleagues hypothesize that, in addition to these known mechanisms, aberrant signaling pathways and metabolic processes of cancer cells are important unexplored mechanisms that could serve as targets. For this reason, – and in contrast to previous projects, which have focused primarily on genetic changes – the researchers in the ExTrAct AML project utilize three independent data sources to create individual risk profiles.

Early identification of patients at risk

First, a team led by Michael Dworzak is applying flow cytometry to create so-called phosphosignal profiles from bone marrow samples. This procedure will reveal the misdirected signaling pathways that lead to the uncontrolled growth of cancer cells. 
Second, the researchers are systematically testing 108 already approved drugs and nine selected combination therapies from a drug database created by experts on leukemia cells in the lab. "We use image-based chemosensitivity screening. This method has the great advantage that in the same experiment we see not only the anti-tumor effect of a treatment, but also how it affects the surrounding cells," explains Ben Haladik, PhD student in Kaan Boztug's group.
Third, by using a machine learning based concept, the (epi)genetic landscape of the leukemia cells – characterized by deep disease profiles using next generation sequencing – as well as clinical parameters are also incorporated into individual profiling.
Another new feature of ExTrAct-AML is that the concept focuses on early identification of patients “at risk”, in contrast to most current precision oncology programs, which mostly include patients at a late stage of the disease.

Pioneering pharmacoscopy in pediatrics

"Together with our project partner, CeMM, we are one of few centers in Europe that have first-hand access to the pharmacoscopy technology," highlights Kaan Boztug. Previously, the Superti-Furga lab has demonstrated the efficacy of pharmacoscopy for the treatment of hematological malignancies in adults. Therapies selected by chemosensitivity testing were able to halt disease progression and resulted in significantly better outcomes than the respective prior therapies (Snijder et al., Lancet Haematol 2017; Kornauth et al., Cancer Discovery 2022). "With pharmacoscopy, we at CeMM have developed an image-based approach to functional single-cell precision medicine – a technology that enables true personalized medicine in cancer treatment. Now we want to test the potential of pharmacoscopy-guided treatment on a broad scale for the benefit of pediatric patients. This is an important milestone," states Giulio Superti-Furga. 

Aim for immediate clinical application

In total, the scientists study bone marrow samples from 45 patients, analyzing at least 50 million cells per patient. In the next step, the team examines the (molecular) signatures obtained in two patient groups of the Italian study group "Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)-AML" and the German study group "AML-Berlin-Frankfurt-Münster". Further analyses from bone marrow samples of 20 AML patients in Austria and Germany will take place in the prospective AIEOP-BFM 2020 study. Michael Dworzak, vice-chairman of the AML-BFM group, adds: "Thus, the ExTrAcT-AML program is embedded in a unique environment of leading clinical experts from national and international AML study centers, which facilitates rapid clinical implementation."

He further notes that this is the first study to combine chemosensitivity and multi-omics data on a specific childhood cancer from a sufficiently large retrospective group as well as a prospective cohort. From the data obtained, the researchers aim to identify patterns of disease progression and treatment resistance. "Despite the genetic diversity of childhood AML, there may be consistent features of disease resistance and progression," explains Kaan Boztug. "We want to provide clinical guidelines for functional ex vivo pediatric precision oncology that can be applied to other disease settings."