Cell Death and Drug Resistance in Lymphoproliferative Disorders

Dr. Santos A. Susin’s laboratory

susin_web_2035

In the era of precision medicine and in a project that aligns with the mission of our Research Center, our team will continue to deepen the research performed in the 2012-2017 period by understanding the mechanisms of drug resistance in Chronic lymphocytic leukemia (CLL) and by translating this knowledge into the development of efficient therapies.

CLL, a human malignancy caused by an imbalance between proliferation and PCD, is the most common form of adult leukemia in Western countries. Drug resistance remains a major cause of treatment failure in CLL and its inevitable fate. The standard front-line therapy (fludarabine, cyclophosphamide, and rituximab), as well as the recent developments implicating BCR and BCL-2 inhibitors, are associated to refractoriness and side effects. Indeed, 15-20 % of CLL patients become refractory to these drugs during the course of the disease. Therefore, (i) a further understanding of the CLL physiopathology; and (ii) the introduction of new drugs inducing cell death via alternative cell death mechanisms could provide new means of improving the current therapeutic strategies. With this in mind, during the las years, we have greatly contributed to the improvement of the current knowledge of the cellular and molecular mechanisms associated to CLL drug resistance:

– From a fundamental point of view, we have: (1) analyzed the origin and the pathogenic mechanisms associated to CLL; (2) scrutinized a robust prognostic CLL biomarkers, the IGHV mutational status; (3) set up a new functional test to detect TP53 dysfunction; and (4) uncovered a new PCD path that is active in the drug resistant CLL B-lymphocytes.

– From an applied perspective, by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with agonist peptides, we have identified a new approach to overcome CLL drug refractoriness.

The main strength of our project is that it involves close interaction between scientists and clinicians, each one taking advantage of the other’s expertise. This cultural and technological exchange entails a multidisciplinary approach that should enable us to meet a two-fold objective. Fundamental: increase the existing knowledge of biochemical and molecular mechanisms associated to drug resistance. Applied/Translational: develop new therapeutic approaches to treat haematological malignancies.

Our Latest News

01 December
Publications and Grants

  – Congrats to Elise and Florence for your paper in American Journal of Hematology...

01 November
Publications and Grants

– Greetings to Lauriane, Audrey and Marie-Noëlle for their excellent CDD paper on...

19 March
CD47-mediated PCD: a promising approach against refractory CLL
read more news

Projects

  • Impact of the BCR structure on CLL drug resistance
  • Genomic alteration characterizing resistant CLL. The example of 2p+
  • Assessment of the key role of TP53 dysfunction in CLL drug-resistant patients
  • CD47-mediated PCD: a promising approach against refractory CLL