Thursday 20th September 2018
Past Research

Bone Marrow Cancer Research



SUPERVISOR: PROFESSOR KRISTIAN BOWLES

PROJECT TITLE:  Investigating cancer stem cells in multiple myeloma

PROJECT TIME SCALE:  1st April 2014 to 31st March 2015

POST DOC: Dr Megan Y Murray

NOVEMBER 2014

MODELLING MYELOMA BONE MARROW
Multiple myeloma is a cancer of the blood and bone marrow, affecting approximately 5000 new patients a year in the DUK. espite advances in therapy which mean that most patients with the disease respond to initial treatment and go into a remission, myeloma at present is incurable because following a response to treatment relapse is inevitable.  The disease relapses because of the presence of (usually) a small population of cancer stem cells (CSC) which are resistant to the chemotherapies currently used. These types of chemotherapy resistant cancer cells are believed to play a particularly important role in blood and bone marrow cancers, like myeloma. During remission CSC can remain in the bone marrow often at low and sometimes undetectable levels. The patient therefore may appear well for months or years but with time these stem cells will eventually proliferate and the cancer will re-grow. By studying and comparing samples taken from patients before and after chemotherapy treatment  we are looking to uncover how these myeloma cells are or become ‘drug-resistant’, which in turn should not only explain relapse but also importantly lead us to new targets for future drug development.In April 2014, Dr Megan Y. Murray (Norwich Medical School) and Professor Kris Bowles (Norwich Medical School and Norfolk and Norwich University Hospital), commenced work funded by a grant from The Humane Research Trust on the presently incurable blood cancer multiple myeloma.

Fig 1: Primary multiple myeloma cells in co-culture with bone marrow stromal cells (BMSC, black arrowheads) from the same patient. Myeloma cells either remain above the BMSC layer(black) or migrae below (red).

Currently, we are working on developing an ‘organotypic’ model system enabling us to study the interaction between myeloma cells, including CSC, with the surrounding bone marrow stromal cells (BMSC) which support them. We use bone marrow donated by patients at our myeloma clinic to create a ‘primary’ co-culture of myeloma cells with BMSC (Figure 1). BMSC provide a ‘scaffold’ for the myeloma cells to grow on and also secrete proteins important for myeloma survival and growth.

Fig 2. Proliferation of myeloma cells and BMSC when cultured alone or in co-culture together. Growing both cell types together triggers significant proliferation of both types. This not only allows us to perform more vital experiments but is also more ‘organotypic ‘, i.e. more physiologically relevant

Figure 2 shows the significant improvement in cell proliferation in co-culture compared to cells cultured alone. This allows us to conduct experiments on myeloma and bone marrow cells which asks questions of how and why the bone marrow environment helps myeloma cancer cells survive chemotherapy at diagnosis and relapse but without the need for animal models.

Recently, thanks to our Humane Research Trust grant, we were able to submit a research paper investigating the role of a new drug, ibrutinib, in the treatment of drug-resistant relapsed multiple myeloma. We believe that ibrutinib is able to specifically target a drug-resistant cancer cell population and provide a scientific rationale for clinical trials of this drug in patients with relapsed myeloma. We expect this work to be available for all to read free of charge when published in an open access peer reviewed journal in the coming weeks.

June 2014 – The Start

Multiple myeloma [MM] is an incurable form of bone marrow cancer with approximately 5,000 people diagnosed each year in the UK. Whilst current MM therapy can successfully induce remission in many patients, disease relapse remains inevitable. This project will use human bone marrow from MM patients to investigate the biologic processes which underpin chemotherapy failure and disease relapse.

Recently we were the first to show that the newly FDA-approved Bruton’s tyrosine kinase [BTK] inhibitor drug, ibrutinib,can enhance the effect of the existing frontline MM chemotherapy, bortezomib,usinghuman MM bone marrow taken from patients in our own clinic.

We now hypothesise that ibrutinibmay be effective in patients with relapsed and drug resistant forms of the disease. In this work we will co- culture the MMcells donated by patients attending our clinic in an environment composed of connective tissue from the same patient [autologous bone marrow stromal cells], also derived from the patient bone marrow sample. This is an attempt to better mimick the human bone marrow microenvironment and permits longer-term culture.We predict samples thatthe BTK survival pathway will be playing an important role in MM cancer cell survival.Furthermore by improving our understanding of the survival pathways we aim to identify other drugable targets in this population with a view to developing biologically plausible therapeutic strategies for this patient group.

This valuable grant will fund a post-doctoral research scientist, with extensive experience of MMbone marrowmanipulation, for 12 months. The immediate impact of this research will be to provide important quantitative data about the pathways that underpin drug resistance in myeloma and specifically build on our previous studies aimed at exploiting ibrutinib,bortezomib and other as yet unknown targets synergistically to improve outcomes in drug-resistant MM.This work iscarried out with the use of primary MM samples from patients with the disease, in a scientific model that does not require animal experimentation.

Author: glewis