The aim of our project is to target Bcl2 and p53 networks in multiple myeloma (MM) and mantle cell lymphoma (MCL) to overcome resistance, as both networks are known to support initial, induced and microenvironment-dependent resistance in both pathologies.
To target Bcl2 network, we propose to assess survival dependency of both MM and MCL cells to Bcl-2 family proteins using BH3 mimetics and BH3 profiling. While the contribution of “omic” approaches is undeniable in our understanding of cancer biology, functional assays such as BH3 profiling could represent the missing link between “omic” results and clinical application for each individual. Because ongoing clinical trials assess safety and efficacy of Bcl-2 and Mcl-1 BH3 mimetics in both pathologies, we propose to study the mechanisms of primary and acquired resistance to BH3 mimetics. To target the extrinsic resistance, we propose to study the microenvironment-mediated regulation of proliferation and survival using RNA sequencing.
Mono or bi-allelic deletion of TP53 or ATM mutations is associated with resistance in MM and MCL, respectively. We propose to perform an integrative analysis of p53 pathway in primary cells (chromosomal deletion, promotor methylation, TP53/ATM mutations, MDM2 amplification, functional “reactivation” of p53 pathway) in order to identify specific targets according to each abnormality. We plan to assess whether new approaches targeting p53 deficiency could be of interest. We will notably explore whether the inability of p53 deficient cells to control methylation-mediated silencing of ancestral integrated DNA and/or to block replication of oncolytic Measles virus is efficient for MM and MCL killing.
The development of tools will include the whole exome sequencing of MM and MCL collections with the aim at the identification of response biomarkers to approved or phase I drugs, the generation of TP53 deleted cells using the CRISPR/Cas9 system, the development of MM and MCL models (in vitro and/or in humanized mice) as well as the characterization of spontaneous canine lymphoma and MM.
C. Pellat-Deceunynck, DR CNRS
M. Amiot, DR CNRS
D. Chiron, CR CNRS
S. Le Gouill, PU-PH
A. Moreau-Aubry, MCU
C. Touzeau, PH
M. Eveillard, PH
A. Lok, PH
P. Gomez- Bougie, IR CHU
B. Tessoulin, Doctorant
A. Papin, Doctoran
Y. Le Bris, Doctorant
A. Papin, Doctorant
C. Seiller,Master 2
S. Vantyghem, Master 2
G. Descamps, IE Univ
C. Dousset, IE CDI CHU
C. Bellanger, IE CDD CHU
S. Maiga, AI CDD CHU
Touzeau C, Dousset C, Le Gouill S, Sampath D, Leverson JD, Souers AJ, Maïga S, Béné MC, Moreau P, Pellat-Deceunynck C, Amiot M. The Bcl-2 specific BH3 mimetic ABT-199 : a promising targeted therapy for t(11 ;14) multiple myeloma. Leukemia. (2014)
Tessoulin B, Descamps G, Moreau P, Maiga S, Lodé L, Godon C, Marionneau-Lambot S, Ouiller T, Le Gouill S, Amiot M, Pellat-Deceunynck C. PRIMA-1Met induces myeloma cell death independently of p53 by impairing the redox balance. Blood. (2014)
Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P, Mathew S, Vijay P, Eng K, Ali S, Johnson A, Chang B, Ely S, Elemento O, Mason CE, Leonard JP, Chen-Kiang S. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. (2014)
Brosseau C, Dousset C, Touzeau C, Maïga S, Moreau P, Amiot M, Le Gouill S, Pellat-Deceunynck C. Vitamin D3 and lenalidomide synergize to induce apoptosis in mantle cell lymphoma via demethylation of BIK. Cell death and disease (2014)
Touzeau C, Ryan J, Guerriero J, Moreau P, Ni Chonghaile T, Le Gouill S, Richardson P, Anderson K, Amiot M, Letai A. BH3-profiling identifies heterogeneous dependency on Bcl-2 family members in Multiple Myeloma and predicts sensitivity to BH3 mimetics.” Leukemia (2015)
Dousset C, Maïga S, Gomez-Bougie P, Le Coq J, Touzeau C, Moreau P, Le Gouill S, Chiron D, Pellat-Deceunynck C, Moreau-Aubry A, Amiot M. BH3 profiling as a tool to identify acquired resistance to venetoclax in multiple myeloma. Brit J Haematol (2016)
Gomez-Bougie P, Halliez M, Moreau P, Pellat-Deceunynck C, Amiot M. Repression of Mcl-1 and disruption of the Mcl-1/Bak interaction in myeloma cells couple ER stress to mitochondrial Apoptosis. Cancer Lett. (2016)
Chiron D, Bellanger C, Papin A, Tessoulin B, Dousset C, Maïga S, Moreau A, Esbelin J, Trichet V, Chen-Kiang S, Moreau P, Touzeau C, Le Gouill S, Amiot M, Pellat-Deceunynck C. Rational targeted therapies to overcome microenvironment-dependent expansion of mantle cell lymphoma. Blood. (2016)
Touzeau C, Le Gouill S, Mahé B, Boudreault JS, Gastinne T, Blin N, Caillon H, Dousset C, Amiot M, Moreau P. Deep and sustained response after venetoclax therapy in a patient with very advanced refractory myeloma with translocation t(11;14). Haematologica. (2017)
Tessoulin B, Eveillard M, Lok A, Chiron D, Moreau P, Amiot M, Moreau-Aubry A, Le Gouill S, Pellat-Deceunynck C. p53 dysregulation in B-Cell Malignancies: more than a single gene in the pathway to hell. Blood Reviews (2017)
Leverson JD, Sampath D, Souers AJ, Rosenberg SH, Fairbrother WJ, Amiot M et al., Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax. Cancer Discov. (2017)
Le Gouill S, Thieblemont C, Oberic L, et al., Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma. NEJM (2017)
Trial of Obinutuzumab,GDC-0199 Plus Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma (OAsIs). PI : Steven Le Gouill. NCT02558816. OPEN
Dose-escalation Study of Oral Administration of S 55746 in Patients With Chronic Lymphocytic Leukaemia and B-Cell Non-Hodgkin Lymphoma. PI : Steven Le Gouill. NCT02920697. Closed
A Study Evaluating ABT-199 in Multiple Subjects Who Are Receiving Bortezomib and Dexamethasone as Standard Therapy (M12). NCT01794507. Closed.
Study Evaluating ABT-199 in Subjects With Relapsed or Refractory Multiple (M13). NCT01794520. Closed
L’HeMa consortium (website under construction)
SIRIC ILIAD (website under construction)