Myeloma - Department of Clinical and Molecular Medicine - Department of Clinical and Molecular Medicine
Multiple myeloma bone disease
One of the hallmarks of multiple myeloma is the presence of osteolytic lesions.
At diagnosis, more than 80% of the patients have osteolytic lesions or severe osteopenia, and during the course of the disease as many as 60% will experience pathological fractures. The bone disease is very painful, leads to severely reduced quality of life and reduced survival. The loss of bone is due to increased numbers and activity of bone-degrading osteoclasts combined with reduced numbers and dysfunction of bone-forming osteoblasts.
Our aim is to understand why this happens. We believe that inflammatory factors present in the bone marrow microenvironment play an important role. Our research activity is therefore also part of the COE, Centre of Molecular Inflammation Research (CEMIR), The bone disease group.
Therese Standal (Project leader), Marita Westhrin, Vlado Kovcic, Kristin Roseth Aass, Glenn Buene
Inflammatory cell death
When a human cell gets old, damaged or excessive, it goes into programmed cell death. This is often a "silent" death.
But if cells are forced into cell death through infections, tissue damage or cytotoxic stress such as cancer drugs or radiation, they will send a danger-alert to the immune system. A cancer cell will repress such danger-alerts, as they can initiate a cancer-killing immune reaction. In our group we try to manipulate immune cells to restore cancer-killing immune reactions.
Kristian K. Starheim (Project leader), Ingrid Nyhus Moen, Erling Håland
The role of the immune system in multiple myeloma
The main goals of the project are to understand at the molecular level how myeloma cells may escape immune surveillance, and how the immune system may be reactivated in the treatment of multiple myeloma.
We do this by analysis of immune cells and mediators in bone marrow and how bone marrow myeloma cells avoid attack by immune cells. We also study how immune cells can be reactivated towards myeloma cells.
Anders Sundan (Project leader), Anne-Marit Sponaas, Rui Yang, Berit Størdal, Hanne Hella
Growth control of myeloma cells
Many factors play important roles in the pathogenesis of multiple myeloma. Our group focuses on how transforming growth factor (TGF)-β superfamily signaling pathways affects myeloma cell growth and survival.
This includes ligands such as TGF-β, activins, BMPs and GDFs. There is extensive redundancy in this superfamily of ligands and receptors, and the effects of a given molecule will always depend on the context. Some of the ligands efficiently induces growth arrest or cell death in myeloma cells. We aim to exploit this to develop novel drugs for treatment of myeloma patients.
Toril Holien (Project leader), Holien, Oddrun Elise Olsen, Nerissa Rae Booc, Martin Haugrud Kastnes
Multiple myeloma genetics
Our research group studies Multiple Myeloma, a cancer arising in the antibody producing plasma cells in the bone marrow.
The primary focus of our research is to understand the genetic and molecular events that occur from the time of diagnosis to the development of a tumor that are refractory to therapy. We use novel methods, such as next-generation sequencing (NGS) of both tumor cells and cell free DNA, as well as well-established cell biology methods. We have access to a large biobank material of purified myeloma cells and cooperate with the Genomics Core Facility at NTNU.
- Monitoring treatment effects, subclonality and drug resistance in Multiple Myeloma by deep sequencing of cellular and cell-free tumor DNA
- Subclonal evolution and bortezomib resistance in multiple myeloma patients
- Mechanisms of bortezomib resistance in multiple myeloma patients
Kristine Misund (Project leader), Anders Waage, Even Holt Rustad
The bone marrow microenvironment in patients with multiple myeloma
Patients with the cancer multiple myeloma have cancer cells primarily growing in the bone marrow, the body’s blood-forming organ. Here they are influenced by other cells and by signaling molecules in their surroundings.
Some of the signaling molecules are so-called cytokines and several of them, e.g. interleukin-6 (IL-6), IL-15 and IL-21, stimulate cancer cell growth. At the same time, the myeloma cells produce molecules that influence the microenvironment to become more hospitable. As an example, we have shown that myeloma cells can contribute to the production of adenosine, a molecule that inhibits immune reactions against cancer cells. The goal of our research is to explore the interplay between myeloma cells and the environment where they live. By all likelihood, the cancer cells are dependent on their bone marrow surroundings, and with our research, we hope to find ways to block signaling molecules that are beneficial to them.
PRL-3, a master regulator of cancer cells
PRL-3 is a relatively small protein that is classified as a phosphatase enzyme. Even though it definitively has phosphatase activity in vitro, it has been difficult to demonstrate PRL-3 substrates in live cells, and the molecule may have important properties unrelated to its enzyme activity. It is clearly demonstrated that PRL-3 is produced by cancer cells and plays an important role by influencing cell signaling events. We have shown that myeloma cells, lymphoma cells and leukemia cells make PRL-3. In these cells, PRL-3 promotes motility and protects against cell death. We have also shown that signaling molecules from the microenvironment, including IL-6 and IL-21, turn on the production of PRL-3 in myeloma cells. Now, we are examining how PRL-3 modulates the turnover of important metabolites in the cells. PRL-3 seems to regulate the production of buildings blocks for DNA and other important macromolecules. In cooperation with researchers from the USA, we test molecules that inhibit the activity of PRL-3. Our goal is that this can be treatment for patients with multiple myeloma and other cancers in the future. CD39, CD73 and adenosine – how myeloma cells block the immune response.
CD39, CD73 and adenosine – How myeloma cells block the immune response
The nucleoside adenosine has emerged as a potent immunosuppressive molecule and represents an attractive new therapeutic target for cancer therapy. Two ectoenzymes, CD39 (ENTPD1) and CD73 (NT5E), are important for converting extracellular ATP to adenosine, where CD39 converts ATP to AMP and CD73 converts AMP to adenosine. Adenosine is immunosuppressive and reduces T cell effector functions such as proliferation and cytokine production. Interfering with the adenosine pathway using anti-CD73 antibodies or antagonists of adenosine receptors on T cells has reduced tumor growth in mice. We will explore the role of adenosine pathway in suppressing anti-tumor responses in myeloma patients with the aim of developing and/or using new drugs to stimulate an efficient immune response that can reduce myeloma cell load either on its own or together with other therapies. This project is a collaboration with Medimmune, AstraZeneca and the Free University of Brussels.
Matriptase - An enzyme with many functions
Matriptase is a protease and is expressed in a wide variety of epithelial tissues. Indeed, it is required for the maintenance of epithelial integrity and normal function. The dysregulation of matriptase is implicated in cancer development and is often associated with poor prognosis. Overexpression of matriptase is found in a range of cancers, and animal studies have shown that the protein is sufficient to cause cancer. In healthy cells, matriptase is always expressed together with its endogenous inhibitor HAI-1. In cancer cells, the ratio between matriptase and HAI-1 is often disturbed. We have found that both matriptase, HAI-1 and the related inhibitor HAI-2 are expressed in multiple myeloma cell lines as well as in patient samples. We have also found that matriptase influences migration in myeloma cell lines, and we are now studying the mechanisms underlying these effects. We will further study the relation between matriptase, HAI-1 and HAI-2 and their importance for the cancer cells.
The overall aim is to find molecular mechanisms to target in future treatment of myeloma.
Magne Børset (Project leader), Torstein Baade Rø, Tobias S. Slørdal, Anne-Marit Sponaas, Pegh Abdollai, Rui Yang, Esten N. Vandsemb, Ida Steiro
Clinical and epidemiological studies
We conduct clinical phase 1-3 trials on drug used in multiple myeloma. Many of the studies are investigator initiated studies in collaboration with the Nordic Myeloma Study Group (NMSG).
Examples of such studies
- Study of ixazomib/len/dex in high dose treatment of multiple myeloma
- Effect of carfilzomib in high dose treatment at first relapse treatment
- Duration of treatment with bisphsphonates in multiple myeloma
- Intensive treatment of patients with plasma cell leukemia
We participate in company initiated trials.
In epidemiological studies we are investigating the occurrence of multiple myeloma and other blood diseases in the near family of patients with multiple myeloma. The basis is 10 000 myeloma patients identified in the Cancer Registry since 1982. We analyse recent trends in incidence and survival of myeloma patients.
Tobias Schmidt Slørdahl (Project leader), Anders Waage, Øyvind Hjertner, Øystein Olstad Langseth, Turid Almvik, Stine Marie Sundt-Hansen.
The role of inflammation in multiple myeloma
Inflammation is an immune response which normally protects during the early phases of infection, but can have harmful effects when dysregulated. Infiltrating immune cells and inflammatory signals triggered in the tumor microenvironment are recognized as important components in driving the progression of multiple myeloma (MM).
Pattern-recognition receptors (PRRs) recognize molecules associated with damage, as well as infection, and are important mediators of inflammatory responses. PRRs mediate immune responses that promote anti-tumor immunity and are beneficial in immunotherapy. Dysregulated PRRs in the tumor microenvironment can, however, potentially promote tumorigenesis by mediating chronic inflammation and fuel tumor growth and metastasis. The outcome of PRR activation in the tumor microenvironment is still unclear.
We aim to provide important insight into how PRR expression and activation affects cancer progression. Knowledge in this field is important in order to block the detrimental effects of PRRs in promoting cancer, and exploit advantageous effects of PRRs in cancer therapy. This should aid early diagnosis and the development of more optimized treatment of MM and is also applicable in other cancers.
Nadra J. Nilsen (Project leader), Marit Bugge