Methods and pharmaceutical compositions for treating cancer

Tumour-specific molecular targets and alternative therapeutic strategies for triplenegative breast cancer (TNBC) are urgently needed. The protease cathepsin D (cath-D) is aberrantly secreted and a marker of poor prognosis in breast cancer. Using degradomic analyses by TAILS, we discovered that the matricellular protein SPARC is a substrate of extracellular cath-D. In vitro, cath-D induced limited proteolysis of SPARC C-terminal extracellular Ca2+ binding domain at acidic pH, leading to the production of SPARC fragments (34-, 27-, 16-, 9-, and 6-kDa). SPARC cleavage also occurred in vivo in TNBC and mouse mammary tumours.
Moreover, the C-terminal 9-kDa SPARC fragment inhibited MDA-MB-231 TNBC cell
adhesion and spreading on fibronectin, and stimulated their migration, endothelial
transmigration and invasion more potently than full-length SPARC. These results highlight a novel crosstalk between proteases and matricellular proteins in the TNBC microenvironment through limited proteolysis of SPARC, and reveal that the 9-kDa C-terminal SPARC fragment is an attractive therapeutic target for TNBC.
Thus, the invention relates to an inhibitor of SPARC fragment for use for treating cancer, and in particularly triple cancer negative breast cancer.

Patent Application number: European Procedure (Patents) (EPA) - 21 Oct. 2020 - 20 306 254.2
Inventors:
LIAUDET-COOPMAN EmmanuelleMALLAVIALLE AudeALCARAZ CACCHIA Lindsay
Publications:
Alcaraz LB Mallavialle A Mollevi C Boissière-Michot F Mansouri H Simony-Lafontaine J Laurent-Matha V Chardès T Jacot W Turtoi A Roger P Guiu S Liaudet-Coopman E. SPARC in cancer-associated fibroblasts is an independent poor prognostic factor in non-metastatic triple-negative breast cancer and exhibits pro-tumor activity. Int J Cancer. 2023 Mar 15;152(6):1243-1258. doi: 10.1002/ijc.34345. Epub 2022 Nov 30. PMID: 36346290; PMCID: PMC10099777.

Reference:

BIO20377-T1

Business Developper
contact
Aymeric Empereur
Business Developer
Rare disease: No
Second indication: No

You might also be interested in