Molecular investigations of mantle cell lymphoma and development of companion diagnostic tools.

The proposed translational project address crucial, specific clinical questions for mantle cell lymphoma patients at distinct stages of the course of disease, such as diagnosis, upon treatment resistance and at relapse. Advanced technologies will be used and combined to pin-point the association between molecular, cellular and clinical parameters with the ultimate goal of developing tools for companion diagnostics.

B cell lymphomas are malignancies where much remains to be achieved in terms of improved treatment. While some subtypes have quite indolent features and good prognosis, others are related to an aggressive clinical course and have only a few years of median survival time. One of the subtypes with the poorest survival is mantle cell lymphoma (MCL), which constitute 6-7% of B cell lymphomas. To enable prolonged survival, early specific diagnosis followed by an aggressive treatment protocol is required. However, despite recent advances, typical MCL patients have a relative poor prognosis with 33% of younger patients surviving for less than five years. Lately, these patients have commonly been treated with combinations of regiments, most often including Rituximab (anti-CD20) in combination with chemotherapy. However, several experimental protocols include very promising new targeted therapies, such as mTOR and BTK inhibitor, and also epigenetic drugs, for example Decitabine and Valproate. The number of potentially effective drugs increases the complexity of designing and evaluating novel clinical protocols for MCL, and companion diagnostic biomarkers/tools for treatment selection in both the front-line and relapsed setting are much needed.

The specific aims of the project are to:

1. At diagnosis: Identify, characterize and validate companion diagnostic biomarkers to allow future prospective stratification of patients into modern combinatorial treatment protocols, such as the Nordic MCL2/3 protocol.
2. Upon treatment resistance: Investigate/address the molecular mechanisms responsible for development of resistance to the nucleoside analogues Cytarabine, and identify predictive markers.
3. At relapse: Identify cellular and molecular markers to predict outcome of patients treated with targeted therapy, to allow optimal treatment selection (Nordic MCL6/Philemon protocol).