Translational research in childhood cancer – Nikolas Herold Research group

Our overall aim is to improve survival in childhood cancer and hematological diseases (histiocytosis).

Our Research

We have several research areas:

  • Translational pediatric cancer research (PI: Nikolas Herold)
  • Histiocytosis (PI: Jan-Inge Henter, see separate tab)

The main goal of our translational approach is to find rationale ways to improve survival in childhood cancer. Our strategy to do so is, first, deciphering the cellular and molecular mechanisms that govern resistance to chemo- and immunotherapy. Second, we develop drugs to target newly found resistance factor. Third, we implement clinical trials to close the translational circle. Childhood cancers that we work with include acute myeloid leukaemia, osteosarcoma and Ewing sarcoma.

Herold laboratory has identified the protein SAMHD1 as a major resistance factor to cytarabine (ara-C) and several other nucleoside analogues, a class of antimetabolites used in the treatment of haematological and solid malignancies. Through a phenotypic screen, we identified the compound hydroxyurea to inhibit the ara-CTPase activity of SAMHD1. A phase 1/2 clinical trial has recently concluded patient inclusion and analysis is pending.

As SAMHD1 has a multifaceted role including tumour suppressor functions coupled to reduction of replication-stress-induced inflammation, we aim to further understand the role of SAMHD1 in different cancers to identify tools to fine-tune its function.

More recently, we try to identify factors that regulate drug-drug interaction of combination therapies including immunotherapy: Here, we focus on osteosarcoma, a disease for which survival has stagnated for four decades.

 

Herold research group
Herold research group Photo: N/A

Staff and contact

Group leader

All members of the group

Alumni

Lars Ährlund-Richter PhD, Professor Emeritus 

Marie Meeths, MD, PhD, Paediatrician

Anna Carin Horne, MD, PhD, Paediatrician

Selma Olsson Åkefeldt, MD, PhD, Paediatrician

Maja Ideström, MD, PhD, Paediatrician

Egle Kvedaraite, MD, PhD 

Alexandra Löfstedt, MD, PhD

Translational pediatric cancer research

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.

SAMHD1 Foto: NA

We also have a strong interest in bone sarcomas and one diagnosis that we currently focus on is Ewing’s sarcoma, a type of solid tumor that can occur in bone or soft tissue and disproportionately affects younger people. The majority of Ewing sarcoma cases express a chimeric fusion protein as a result of an oncogenic translocation. Combining different techniques, we are developing strategies to target this oncogenic driver of Ewing sarcoma. Our preliminary results indeed indicate that we can successfully target the fusion protein and more efficiently kill sarcoma cells.

The second bone sarcoma we work on is osteosarcoma, the most common type of malignant bone tumours in children, adolescents and young adults. Despite several international studies with the aim to improve the outcome, survival for osteosarcoma has stagnated for four decades.

In order to get a better understanding of why 30-40% of osteosarcoma patients respond insufficiently  to standard treatment, we are investigating the response to commonly used drug combinations in various osteosarcoma cell lines and correlate this with gene expression.

Another strategy that we pursue for osteosarcoma is the possibility to combine novel immunotherapy with conventional chemotherapy. Despite anecdotally highly efficient against osteosarcoma, up to now immunotherapy has shown no to moderate clinical effects for this diagnosis. We hypothesize that by finding the right combination of immunomodulating drugs, osteosarcoma can once more become the paradigmatic example for successful immunotherapy.

Histiocytosis

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.

Hemophagocytic lymphohistiocytosis (HLH)

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.

Langerhans Cell Histiocytosis (LCH)

Langerhans cell histiocytosis (LCH) is a potentially fatal disease with a highly variable clinical picture. Bone and skin are the most common organs affected, and other organs that may be involved include the liver, spleen, bone marrow, lungs and CNS. CNS involvement often causes endocrine affection, and sometimes a slowly progressive, potentially devastating, neurodegeneration. Together with Sahlgrenska University Hospital in Gothenburg we have developed valuable tools for assessing and monitoring neurodegenerative CNS-LCH. Our aims are to elucidate etiology and pathophysiologic mechanisms of LCH, and to reduce mortality and late effects.

The classical treatment typically involves mild chemotherapy, such as vinblastine, methotrexate, 6-mercaptopurine, corticosteroids, and vincristine, but very toxic chemotherapy such as high doses of cytarabine and 2-CdA in combination have been suggested as salvage therapy regimens.

LCH is currently viewed as an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Importantly, targeted inhibition of the MAPK pathway has improved survival further. The therapeutic effect in neurodegenerative CNS-LCH, which affects > 20% of all LCH patients and also causes most of the severe late effects, is still not well known.

One current aim is to improve survival and reduce late effects. We participate actively in the international multicenter study LCH-IV on treatment and natural history of pediatric LCH patients, in which we coordinate the part on CNS-LCH. We also evaluate targeted inhibition of the MAPK pathway in LCH in general and with regard to CNS-LCH. We also study inactivation of drugs used in LCH, and how to reduce such inactivation. Another current aim is to better understand the underlying biology causing LCH.