Optimising Targets and Therapeutics in High Risk and Refractory Multiple Myeloma

Research in bone marrow microenvironment

Researchers have to date focused on therapy aimed primarily at the cancer cells, but recently, however, scientists have realised that not enough attention was being paid to the impact of the bone marrow microenvironment on multiple myeloma. The microenvironment often provides a protective niche for the tumour and in many cases optimal conditions for growth. The concept of the OPTATIO (OPtimizing TArgets and Therapeutics In high risk and refractOry Multiple Myeloma) project is to develop tools to interfere with the cancer microenvironment and in this way improve the chances of therapy in the fight against multiple myeloma.

OPTATIO is an EU project under Framework Programme 7 and brings together the expertise from twelve partner institutions from Austria, Germany, the Czech Republic, Italy, Hungary, and Spain. The scientific coordinator is Dr Wolfgang Willenbacher from Innsbruck Medical University, Innsbruck, Austria. The project has assembled an international scientific collaborative consortium, combining the expertise of academic, clinical, small and medium enterprises, and industrial partners to achieve the project's objectives.

Microenvironment boosts resistance

Multiple myeloma cells grow in niches in the bone marrow. They are surrounded by tissue cells, bone marrow cells (osteoblasts and osteoclasts), blood vessel cells and immune cells. These cells stimulate each other in a highly interactive way by close contact and soluble factors. There is a regular interplay and exchange of messenger substances, e.g. cytokines. Genes are activated so that even more cytokines are produced and a self strengthening cycle exists. This assists in helping cancer cells to “hide” and avoid cell death which should normally be the result of medication. The explanation of this resistance mechanism is one of the aims of OPTATIO.

A further aim of OPTATIO is to investigate whether the microenvironment is responsible for the fact that this cancer develops from an obligatory precursor stage, monoclonal gammopathy of unknown significance (MGUS), which is often identified in the older generation (up to 3% of people over 60 years old) and is mostly harmless. However in 1% of cases per year, this precursor stage develops into multiple myeloma. The deciding factors for progression into multiple myeloma are not yet well understood. This will also be investigated within OPTATIO.

A new type of testing platform and entirely a new level of verification of the results

The OPTATIO project is developing a new type of testing platform that incorporates both cancer cells and micro-environment: tissue cells, bone marrow cells, blood vessel cells and immune cells. In essence, these support cells serve as the soil in which the seed of cancer grows.

Researchers have already created realistic “co-culture” systems of both seed and soil, but what OPTATIO project introduces is an entirely new level of verification of the results. Through partnerships with clinicians the team has collected cells from hundreds of myeloma patients across Europe. Since clinical data also exist on these patients – including information about which drugs they responded to and how – the results between cell culture and real-life patient can be compared to get as close a replica as possible.

In addition, co-culture systems could allow researchers to test a new approach to drug therapy: perturbing the cancer’s “soil” rather than attacking the cancer cells directly. This is a promising improvement since drugs that target the cancer cells often do not kill all of them, and can thus encourage drug resistance. “Drugs will always target only a proportion of the disease, and so there is a lot of selective pressure on these cells,” says project coordinator Wolfgang Willenbacher at Innsbruck Medical University in Austria. “We feel the environment might be a much more constant variable,” he adds.

The industrial partners involved in the project initially provided thousands of compounds that were tested in the co-culture systems. Two primary categories of potential drugs tested were kinase inhibitors, which block enzymes crucial for cancer cells to multiply, and natural marine substances.

From that original testing, the researchers identified several promising candidate compounds to bring to the next stage of drug testing, in mice. That part of the project is underway now. Depending on how the tests go, the team expects to have at least one, and maybe more, drugs ready for phase I clinical trials by the end of 2014.

Information source

FP7 OPTATIO Project. Page visited on 3 March 2014.