Scientific project


 

Eradication of the last tumor cell has been the holy grail of cancer research for decades. The idea was that if only a few persistent cancer cells remain in the body, relapse would inevitably occur. Thus, understanding the mechanisms that allow for the long-term persistence of these cells would help to avoid relapses. To address the question of persistence in human leukemia, we have built our research team around two strategic scientific axes. The first axis was aimed at discovering, using experimental models, factors that govern tumor dormancy in leukemia. The second axis was dedicated to the systematic evaluation of new genomic markers of prognosis in leukemia. Team 3 is now moving forward using Next Generation Sequencing technologies, pharmacogenomic, and drug targeting of dormant leukemia cells.

Main achievements and themes

A) Genomic of myeloid malignancies (Project Leader Claude Preudhomme).

1- Genomic markers of prognosis

The characterization of potential predictive markers of treatment failure and relapse in hematological malignancies has to yield results that can be easily translated into the daily routine. To fulfill this objective, we strengthened our links with clinical collaborative study groups (e.g. ALFA http://www.alfa-leukemia.fr/ ). Biobanking of numerous national prospective clinical trials, is done in our team at the tumor cell bank (Tumorothèque CHU Lille, Pr. Claude Preudhomme). This offer to us a powerful tool to explore and validate genomic markers. We now focused on NGS techniques, through intense collaborations with the high throughput genomic common facility of University. Team 3 members developed genomic projects both in team and in the platform, in collaboration with its bioinformatic engineers.

Some examples of genomic markers translated in daily routine:

- BCR-ABL MRD evaluation in imatinib plus interferon in the SPIRIT trial: (Preudhomme et al, N Engl J Med 2010;363:2511-2521).

- IDH1 and IDH2; TET2; RUNX1; DNMT3a; WT1; MyD88 (see main publications list)

2- Pharmacogenomic of Acute Myeloid Leukemia (Project leader Meyling Cheok)

In 2008, Meyling Cheok joined our team, after nine years at St Jude Children’s Research hospital in Memphis. She developed in this previous institution a genome wide strategy of pharmacogenomics of Acute Lymphoblastic Leukemia (ALL). Global gene-expression profiling can identify genes with levels of expression that are related to cytotoxic drug response. This methodology led to the identification of several mechanisms of drug resistance in ALL (Cheok et al, Nature Review Cancer 2006).. Meyling Cheok started to translate her expertise in AML as drug resistance appears as a key mechanism of MRD persistence. A project studying blast samples from patients included in clinical trials from the ALFA collaborative study group has been initiated.

B) Leukemia persistence and tumor dormancy. (Project leader Bruno Quesnel)

The phenomenon of long-term persistence of cancer cells that do not grow is called tumor dormancy. Few experimental models of tumor dormancy are available, and dormant tumor cells in humans are extremely difficult to isolate, making scientific progress relatively slow. To understand the mechanisms that govern tumor dormancy in acute myeloid leukemia, we built several mouse models of leukemia dormancy. Mice in complete remission after one year show a few dormant tumor cells, usually no more than 1,000, and sometimes no more than 100. When these cells are isolated and injected into naïve mice, they can still induce AML. The fact that the dormant tumor cell population remained stable in immune hosts indicates that residual cells must avoid elimination by the host’s immune response. We demonstrated that over time, dormant tumor cells became more resistant to specific CTL-mediated killing. From that, we discovered several mechanisms of immunoescape (PD-L1, CCL2) and resistance to cell death (GILZ, SOCS1). We focus now on whole genome sequencing of dormant tumor cells to determine clonal evolution during dormancy.

We also started collaborations with other teams to extend the field to some solid tumors, like malignant melanoma (Team 4, R. Polakowska). We also recently started collaborations with teams specialized in drug design and pharmaceutical chemistry to elaborate new drugs with the aim to selectively target dormant tumor cells. A common project to study tumor dormancy in large animals (dogs) with the veterinarian oncology clinic ONCOVET http://www.oncovet-clinical-research.com/ are also under way. These projects are part of building of the SIRIC OncoLille project (Lille Comprehensive Cancer Center).