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IMM Project Awarded with APCL research Grant

October 13, 2014

The project "Preprogrammed versus stochastic clonal evolution of relapsing Acute Myeloid Leukaemia: Impact on disease development and therapeutic responses" will dissect why the subpopulations of primary human blood cancer cells that drive leukaemic relapse resist relevant clinical treatments in vivo. Ultimately the results will help the field of cancer research to learn how to combine and develop different therapies to achieve better clinical outcomes for leukaemia patients.

The key to better long-term patient outcomes and cure is to learn how to prevent cancer from returning. The first step is to understand how a small fraction of the tumour cells often escape therapy while becoming more malignant. According to Håkan Norell, senior staff scientist in Bruno Silva-Santos Lab at the IMM and the principal investigator of the research project, this grant will allow the team to "in unprecedented depth understand why certain leukaemia cells resist specific therapies, thereby enabling us to design strategies to counteract tumour escape in the future".

For this project, the IMM research team — constituted by Håkan Norell, Bruno Silva-Santos (group leader at IMM), Francisco Caiado (post-doc in the Silva-Santos Lab) and Tânia Carvalho (director of IMM's Histology & Comparative Pathology Laboratory) — will work closely with Maria Gomes da Silva (director of the Haematology department at the IPO-Lisbon (Portuguese Institute of Oncology) who will supervise a team of clinicians, responsible for seeing all the acute myeloid leukaemia (AML) patients admitted to IPO.

About the research project
Standard chemotherapy treatment successfully eliminates almost all the tumour cells in most AML patients. This notwithstanding the disease returns after a number of months in many patients achieving such "complete remissions". One underlying reason is that all tumours consist of a collection of very many somewhat heterogeneous cancer cells. When we apply a strong selective pressure (like an anti-tumour chemotherapy), some of the leukaemia cell variants may thus be selected for, in a Darwinian-manner (survival of the fittest), to then drive the tumour relapse. Accordingly, the relapsing leukaemia is often even more aggressive than the original disease and only around 10% of AML patients survive a tumour recurrence.
Genome comparison of matched primary and recurring AML has shown that selection/ expansion of certain pre-existing clonal tumour cell variants synergized with de novo mutations to fuel emergence of therapy-resistant lethal relapses. The dominant genetic alterations influencing the prognosis of AML have been largely characterized. In contrast, little is known about the impact of (sub)clonal interference and evolution on the recurrence and success of re-treatment in cancer. This is largely due to the lack of experimental systems that allow interactive studies of tumour escape variant development, in particular with the resolution of single founder cells.
The research project will resolve this bottleneck in the understanding of oncobiology by using a highly sophisticated "cellular barcoding" technology. The barcoding allows large scale parallel lineage tracing and thereby enable us to dissect the subclonal dynamics that drive relapse of different primary human AML after in vivo treatment. By re-transplanting the AML cells that relapse after different treatments, we will further determine how the various subclonal architectures generated impacts disease progression and responses to re-treatment.

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