OPTATIO

OPtimizing TArgets and Therapeutics In high risk and refractOry Multiple Myeloma

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 Obiettivo del progetto (Objective)

'Multiple Myeloma (MM) is an incurable disease with rapidly growing prevalence and poor prognosis. Consequently, it is the goal of the OPTATIO consortium to seek out novel strategies for the development of novel diagnostic and therapeutic options. The MM pathogenesis involves not only genetic changes within the tumour cells but also the emergence of supportive conditions by the bone marrow microenvironment (BMM). To target the essential components of this support system, it is the goal of the project to establish preclinical in vitro and in vivo models of MM that include functionally relevant elements of the BMM. The OPTATIO consortium will therefore analyse clinical data to correlate the presence of particular MM-BMM interactions with the pathogenesis of MM, with its intrinsic therapy resistance as well as with disease relapse due to the development of acquired drug resistance. These correlative data will be validated using autologous MM-BMM co-culture assays and reverse translated into in vitro screening and in vivo models, which will be subsequently used to develop lead compounds that target myeloma cells within their microenvironment. The clinical expertise of several oncological divisions, the research experience of academic laboratories and the pharmaceutical know-how of small and medium sized enterprises as well as biotech industry joined their efforts within the OPTATIO consortium to drive this important development and to ensure translation towards clinical trials. Expected impacts of the project include establishment of better diagnostics, new drug screening approaches for MM and novel personalised therapies based on individual ex vivo phenotyping leading to reduced patient mortality. Since envisaged drug screening methods are applicable to other areas of research and development, the project results will open new markets for industry partners in the fields of drug discovery and pharmaceutical development of products and services for personalized medicine.'

Descrizione progetto (Article)

Two thirds of MM cases develop in older patients and they are nearly always incurable. It is a tumour of the immune system that develops from mature antibody-producing B cells.

MM cells grow in niches in the bone marrow. They are surrounded by tissue cells, bone marrow cells, blood vessel cells and immune cells. The BMM helps cancer cells to avoid cell death, thereby making them refractory to medication.

The MM pathogenesis involves not only genetic changes within the tumour but also the emergence of supportive conditions by the BMM. The goal of the EU-funded 'Optimizing targets and therapeutics in high risk and refractory multiple myeloma' (http://www.optatio.eu/ (OPTATIO)) consortium is to target the essential components of this support system.

In the project preclinical in vitro and in vivo models of MM are developed that include functionally relevant elements of the BMM. Clinical data analysis correlates the presence of particular MM-BMM interactions with the pathogenesis and therapy resistance of MM. These data are validated using autologous MM-BMM co-culture assays. In vitro drug screening and in vivo models will be subsequently used to develop lead compounds that target myeloma cells within their microenvironment.

Initially, the consortium created a bank of more than 3000 tumour samples with the database for efficient distribution. Inclusion of BMM into co-culture models was achieved by improvement of 2D co-culture technique and multi-cell type 3D spheroid assays.

Researchers carried out several stages of screening for anti-MM compounds. It included compounds as well as natural product libraries. Compound library screening identified 20 lead candidates. Analysis of marine extract libraries is currently underway.

The consortium developed a murine MM model for the final stage of the in vivo screening. Another developed model employs primary MM cells in mice with a humanised haematopoiesis. This would allow transfer of MM cells autologous to the engrafted human stem cells to study MM-BMM interactions.

Information about OPTATIO progress is regularly disseminated at scientific meetings. Experimental results were presented so far in 15 publications. Expected impact of the project includes better diagnostics, new drug screening approaches and effective personalised therapies for MM treatment.