PROJET MI-RIOT 4

Ce projet MI-RIOT est porté par le centre cardiovasculaire et nutrition, l’INSERM et le CIML

CONTEXT

SOLUBLE CD146: diagnostic tool and therapeutic target in tumors over-expressing cd146.

CD146 is a membrane glycoprotein neo-expressed on many tumors (melanoma, colon, prostate, breast, pancreas, …). It is associated with an increased invasion and dissemination and thus constitutes a factor of bad prognosis. We have identified soluble CD146 (sCD146) as a new factor generated by the shedding of the membrane form. Of interest, it is highly secreted by CD146-positive tumors. This factor displays both autocrine effects on cancer cells and paracrine effects on endothelial and immune cells, promoting tumor angiogenesis, growth and dissemination.

Glioblastoma is a highly aggressive and malignant grade IV tumor that originates from astrocytes in the Central Nervous System. Despite the multifaceted therapeutic interventions, including chemo, radio, and immuno-therapies, it remains the most resistive and lethal tumor among primary brain tumors. Currently, Avastin, an anti-VEGF monoclonal antibody, is the most common therapy prescribed for newly diagnosed patients. However, glioma tumor cells have developed manifold mechanisms to counteract the anti-angiogenic effect of this drug.

OBJECTIVES

We thus tested the hypothesis that sCD146 could participate in these escape mechanisms in glioblastoma. In addition, we decided to generate a humanized anti-sCD146 antibody able to block the effects of the molecule.

RESULTS

For the first time, we have demonstrated that sCD146, which plays a major role in resistance to current chemotherapies, is secreted by different Glioblastoma cells, particularly in response to avastin. We have also shown that targeting sCD146 with mucizumab, our novel humanized anti-sCD146 mAb, not only protects from the aforementioned effects but also allows an additive therapeutic effect with Avastin in a mouse model of subcutaneous xenografting of the glioblastoma cells. This could constitute a key breakthrough in Glioblastoma therapy.

Other experiments are currently in progress to confirm the effects of the antibody after orthotopic injection of the cells.

PUBLICATIONS

1. Maeva Dufies, et al. Soluble CD146 is a predictive marker of pejorative evolution and of sunitinib efficacy in clear cell renal cell carcinoma. Theranostics; 2018; 8(9): 2447-58.

2. Anais Moyon, et al. Early prediction of revascularization by angiomotin targeting positron emission tomography. Theranostics; 2018; 8(18):4985-94.

3. Nollet M, et al. A novel anti-CD146 antibody specifically targets cancer cells by internalizing the molecule. Oncotarget. 2017; 8(68):112283-96.

4. Wael Traboulsi*, Jimmy Stalin*, et al. Therapeutic targeting of soluble CD146/MCAM with the M2J-1 monoclonal antibody prevents metastasis development and procoagulant activity in invasive tumors. International Journal of Cancer; 2020; 147(6):1666-79.

5. Ahmad Joshkon Jimmy Stalin, et al. J Cell Immunology ; 2020; 2(3): 116-23.

PATENTS

1. Methods and kits for predicting the sensitivity of a subject suffering of renal cancer to sunitinib. M. DUFIES, N. BARDIN, F. DIGNAT-GEORGE, G. PAGES, M. BLOT-CHABAUD. Patent number: 17305972.6-1405.

2. Radiolabeled soluble CD146, preparation and uses thereof. B. GUILLET, M. BLOT-CHABAUD, F. DIGNAT-GEORGE, P. GARRIGUE, J. STALIN, A MOYON. Patent number: 17305198.8-1453.

3. Human soluble CD146 proteins, preparation and uses thereof. M. BLOT-CHABAUD, M. NOLLET, R. BACHELIER, N. BARDIN, F. DIGNAT-GEORGE. Patent number: 17306271.2-1410.

4. Anti-CD146 antibodies and uses thereof. M. BLOT-CHABAUD, B. GUILLET, M. NOLLET, J. STALIN, N. BARDIN, F. DIGNAT-GEORGE. Patent number: 17306348.8-1403.