Translational research in childhood cancer – Nikolas Herold Research group

• Overcoming chemotherapy and immunotherapy resistance in childhood cancer. PI: Nikolas Herold.
• Hemophagocytic lymphohistiocytosis (HLH) and Langerhans cell histiocytosis (LCH). PI: Jan-Inge Henter.
• Epitranscriptomics in acute lymphoblastic leukemia. PI: Frida Holm
• Spatial multi-omics and heterogenity in neuroblastoma. PI: Shahrzad Shirazi Fard

These are the questions that drive our research. Our overall aim is to identify resistance factors that limit the effecicay of chemotherapy or immunotherapy, develop new treatment strategies that target those resistance factors and translate them into clinical trials for better treatment of children with cancer.

Our team has identified the protein SAMHD1 as a key regulator of resistance to antimetabolites, a class of drugs regularly used against e.g., leukemias. By a small-molecule screening, we identified the compound hydroxyurea to inhibit SAMHD1 activity. Since hydroxyurea is already approved in the treatment of several cancer forms, this could relatively fast be translated into a clinical study that is currently ongoing (https://news.ki.se/breakthrough-in-precision-medicine-for-the-treatment-of-acute-myeloid-leukaemia, https://www.onkologiisverige.se/billigt-lakemedel-kan-motverka-behandlingsresistent-leukemi/). We have also several pre-clinical projects investigating the role of SAMHD1 in different malignancies.

Since SAMHD1 has a complex role in the cell with functions that can be either good or bad for cancer depending on the context, we aim to further understand the role of SAMHD1 in different diseases and to identify tools to fine-tune its function.

The mononuclear-phagocyte system comprises two major cell types, the macrophages and the dendritic cells, which are mainly antigen-presenting cells. Accordingly, histiocytoses are classified as either diseases with macrophage accumulation, including (familial) hemophagocytic lymphohistiocytosis (FHL or HLH), or disorders with the antigen-presenting Langerhans cell as the central cell, with Langerhans cell histiocytosis (LCH), previously called Histiocytosis X, as the most frequent disease.

Primary (genetic) HLH / familial HLH (FHL)

We have a deep and long-lasting interest in this field. FHL is a rapidly fatal disease that most typically affects infants and young children, with a median survival of 1-2 months without treatment. We have developed the international diagnostic guidelines for HLH (1991 and 2004) and, in collaboration with clinical scientists worldwide, we coordinated the international treatment protocols HLH-94 and HLH-2004 with the major aim to improve the therapeutic results.

In 1996 we suggested that FHL might be caused by an apoptosis defect and in 1999 we were able to show that FHL is caused by a deficiency in apoptosis triggering. Subsequently, in collaboration with other research groups in 1999, mutations in the perforin gene (PRF1) were revealed in a subset of FHL patients. Additional genetic studies revealed another gene causing FHL (STX11), and a deep intronic mutation and an inversion of the gene UNC13D.

Interestingly, it appears as if mutations in FHL-causing genes may be associated with an increased risk of developing malignancies, and we have shown that this is the case also for healthy carrier of FHL-causing genes, possibly due to a moderately deficient surveillance of tumor transformed cells.

Currently we aim to improve diagnostics of FHL and to improve treatment strategies of patients with primary HLH. We are also interested in exploring if carriership of FHL genes is associated with other health problems.

Secondary (acquired) HLH

The clinical hallmark of HLH is massive inflammation (“hyperinflammation”). We are increasingly interested various forms of secondary HLH, including infection-associated HLH, malignancy-associated HLH and rheuma-associated HLH, in children as well as adults. In international collaboration, we have recently prepared recommendations for the use of etoposide-based treatment in secondary HLH, recommendations for management of HLH in adults, and recommendations for management of HLH in intensive care units (ICU).

Our current studies aim to improve survival in infection-associated HLH (including dengue-HLH), malignancy-associated HLH, rheuma-associated HLH and HLH in the ICU. We also aim to understand the underlying biology causing secondary HLH.  

We want to take advantage of our solid knowledge on HLH and hyperinflammation, and expand that knowledge to other relevant patient groups. Our ultimate goal is to improve the outcome, in all respects, of patients affected by hyperinflammation.

We aim to decipher the complicated interplay between different cell types within the paediatric tumour neuroblastoma in order to investigate consequences of heterogeneity for the progression into refractory disease. We do so by a series of methodological refinements where we, on the same biopsy section, combine Spatial multi-omic techniques targeting DNA, RNA, and Protein at single-cell resolution. This is coupled with super-resolution microscopy and development of analyzing tools for simultaneous localization of targets in thousands of cells. Our research aims to provide a comprehensive repertoire of tools for studying tumour heterogeneity, while mapping the spatial principles that guide how tumour cells respond to treatment.