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Thematic 3

Thematic 3

Validation and Identification of New Targets in cancer and AGEing  (VINTAGE)

The strategy of our team is to identify and validate potential diagnostic and therapeutic targets through three highly interconnected themes: 1. Search for specificities of older patients with cancer; 2. Therapeutic targeting in cancer and ageing; 3. The role of inflammation in the development of cancers.

The first theme is approached in clinical research programs regarding the refinement of the patients’ selection process to personalize treatment according to patient’s characteristics: currently performed by the Comprehensive Geriatric Assessment (CGA) test, we shown that it may be improved through the identification of diagnostic markers of frailty as well as predictors of response to treatment and toxicity; the use of innovative targeted therapies, derived from a better understanding of the biology of cancer in the elderly may also allow for optimized efficacy / toxicity ratio.

Therapeutic targeting of cancers subtypes is studied by two subgroups: the “Novel mediators of lung oncogenesis” subgroup use mouse models to characterize new signalling pathways and oncogenic functions that govern the onset and progression of lung adenocarcinoma (LUAD). Up to now, the development of precision therapies has not been possible for the most abundant LUAD patient group: those harbouring KRAS mutations. The main goal is to better understand KRAS biology to identify potential tumour-specific vulnerabilities. In this respect, mechanisms that regulate the intensity and duration of the RAS-ERK signalling are investigated ; the ongoing research also concern the validation of KRAS dimerization as an essential oncogenic function. This later finding could have potential therapeutic application. The “AGR, Tumor Niche & Secretome” (ARTiSt) subgroup aims at understanding how tumor cells initiate and maintain a tumor niche which favors tumor development. In particular, the works focus on the Anterior GRadient (AGR) family of proteins which act on the tumor niche through 2 different modes including intracellular and extracellular functions. This occurs either intracellularly via the control of Endoplasmic Reticulum (ER) proteostasis, by affecting tumor or stromal cells secretomes, or extracellularly, when AGR proteins are secreted and act as pro-oncogenic factors.

Last, research regarding the role of inflammation in the development of cancers focus on a recent finding : in an inflammatory context, the production of cleaved-CD95L by endothelial cells (demonstrated in the blood of patients with Triple Negative Breast Cancer, besides other pathologies) promotes cell migration through a Ca2+-driven signaling pathway, with an increased risk of developing metastases. Therapeutic approaches targeting this CD95-mediated calcium response were designed and are currently under evaluation in murine models of cancers and inflammation.

 

Publications VINTAGE

1: Fessart D, Domblides C, Avril T, Eriksson LA, Begueret H, Pineau R, Malrieux C, Dugot-Senant N, Lucchesi C, Chevet E, Delom F. Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties. Elife. 2016 ; 5 : e13887.

2: Poissonnier A, Sanséau D, Le Gallo M, Malleter M, Levoin N, Viel R, Morere L, Penna A, Blanco P, Dupuy A, Poizeau F, Fautrel A, Seneschal J, Jouan F, Ritz J, Forcade E, Rioux N, Contin-Bordes C, Ducret T, Vacher AM, Barrow PA, Flynn RJ, Vacher P*, Legembre P*. CD95-mediated calcium signaling promotes T helper 17 trafficking to inflamed organs in lupus-prone mice. Immunity 2016 ; 45 : 209-23. (*Co-senior author)

3: Villar VH, Nguyen TL, Delcroix V, Terés S, Bouchecareilh M, Salin B, Bodineau C, Vacher P, Priault M, Soubeyran P, Durán RV. mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation. Nat Commun 2017 ; 8 : 14124.

4: Nieto, P., Ambrogio, C., De Esteban, L., Gómez-López, G., Blasco, T., Yao, Z., Marais, R., Rosen, N., Chiarle, R., Pisano, D.G., Barbacid, and Santamaría, D. A B-Raf kinase inactive mutant induces lung adenocarcinoma. Nature 2017; 548, 239-43.

5: Kraeber-Bodéré F, Pallardy A, Maisonneuve H, Campion L, Moreau A, Soubeyran I, Le Gouill S, Tournilhac O, Daguindeau E, Jardel E, Morineau N, Bouabdallah K, Gyan E, Moles MP, Gressin R, Berthou C, Sadot S, Moreau P, Deau B, Bodet-Milin C, Cazeau AL, Garin E, Salaun PY, Vuillez JP, Gouilleux-Gruart V, Barbet J, Wegener WA, Goldenberg DM, Lamy T, Soubeyran P. Consolidation anti-CD22 fractionated radioimmunotherapy with 90Y-epratuzumab tetraxetan following R-CHOP in elderly patients with diffuse large B-cell lymphoma: a prospective, single group, phase 2 trial. Lancet Haematol 2017 ; 4 : e35-e45.

6: Ambrogio, C., Köhler, J., Zhou, Z., Wang, H., Paranal, R., Li, J., Capelletti, M., Caffarra, C., Li, S., Gondi S., Hunter, J.C., Chiarle, R., Santamaría, D.*, Westover, K.D.* and Jänne, P.A.* KRAS dimerization impairs sensitivity to MEK inhibitors and is essential for oncogenic activity of mutant KRAS. Cell 2018; 172(4), 857-68.e15. doi: 10.1016/j.cell.2017.12.020. (* Co-senior authors)

7: Nguyen TL, Nokin MJ, Egorov M, Tomé M, Bodineau C, Primo CD, Minder L, Wdzieczak-Bakala J, Garcia-Alvarez MC, Bignon J, Thoison O, Delpech B, Surpateanu G, Frapart YM, Peyrot F, Abbas K, Teres S, Evrard S, Khatib AM, Soubeyran P, Iorga BI, Durán RV*, Collin P. mTOR inhibition via displacement of phosphatidic acid induces enhanced cytotoxicity specifically in cancer cells. Cancer Res 2018 ; 78 : 5384-97. (*corresponding author).

8: Delcroix V, Mauduit O, Tessier N, Montillaud A, Lesluyes T, Ducret T, Chibon F, Van Coppenolle F, Ducreux S, Vacher P. The role of the anti-aging protein klotho in IGF-1 signaling and reticular calcium leak: impact on the chemosensitivity of dedifferentiated liposarcomas. Cancers (Basel) 2018 ; 10 : 439.

9: Beauvarlet J, Bensadoun P, Darbo E, Labrunie G, Rousseau B, Richard E, Draskovic I, Londono-Vallejo A, Dupuy JW, Nath Das R, Guédin A, Robert G, Orange F, Croce S, Valesco V, Soubeyran P, Ryan KM, Mergny JL, Djavaheri-Mergny M*. Modulation of the ATM/autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells. Nucleic Acids Res 2019 ; 47 : 2739-56. (*corresponding author)

10: Le Morvan V, Richard E, Cadars M, Fessart D, Broca-Brisson L, Auzanneau C, Pasquies A, Mathoulin-Pélissier S, Lansiaux and Robert J. Cytochrome P450 1B1 polymorphism drives cancer cell phenotype and patient outcome in head-and neck carcinoma. Br J Cancer. 2020 Jun. doi: 1038/s41416-020-0932-5.