Predictive gene signature of response to the anti-TweakR mAb PDL192 in patient-derived breast cancer xenografts.

Abstract

PURPOSE:

(1) To determine TweakR expression in human breast cancers (BC), (2) evaluate the antitumor effect of the anti-TweakR antibody PDL192, used alone or after chemotherapy-induced complete remission (CR), on patient-derived BC xenografts (PDX) and (3) define predictive markers of response.

EXPERIMENTAL DESIGN:

TweakR expression was analyzed by IHC on patients and PDXs BC samples. In vivo antitumor effect of PDL192 was evaluated on eight TweakR-positive BC PDXs alone or after complete remission induced by a combination of doxorubicin and cyclophosphamide. Using both responding and resistant PDX tumors after PDL192 administration, RT-QPCR were performed on a wide list of selected candidate genes to identify predictive markers of response.

RESULTS:

TweakR protein was expressed in about half of human BC samples. In vivo PDL192 treatment had significantly anti-tumor activity in 4 of 8 TweakR-positive BC PDXs, but no correlation between the expression level of the Tweak receptor and response to therapy was observed. PDL192 also significantly delayed tumor relapse after CR. Finally, an 8 gene signature was defined from sensitive and resistant PDXs.

CONCLUSIONS:

PDL192 was highly efficient in some BC PDXs. We found 8 genes that were differentially expressed in responding and resistant tumors and could constitute a gene expression signature which would need to be extended to other xenograft models for confirmation. These data confirm the therapeutic potential of TweakR targeting in BC and the possibility of prospectively selecting patients who might benefit from therapy.

• Authors: Ludmilla de Plater, Anne Vincent-Salomon, Frédérique Berger, André Nicolas, Sophie Vacher, Eléonore Gravier, Aurélie Thuleau, Narjesse Karboul, Marion Richardson, Clément Elbaz, Elisabetta Marangoni, Ivan Bièche, Xavier Paoletti, Sergio Roman-Roman, Patricia A Culp, Bernard Asselain, Véronique Diéras, Didier Decaudin
• Journal: PloS one (PLoS One) Vol. 9 Issue 11 Pg. e104227 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25375638 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Receptors, Tumor Necrosis Factor
• TWEAK Receptor
• Doxorubicin
• Cyclophosphamide
• enavatuzumab

Topics

• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cyclophosphamide (therapeutic use)
• Doxorubicin (therapeutic use)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Middle Aged
• Receptors, Tumor Necrosis Factor (genetics, immunology, metabolism)
• TWEAK Receptor
• Treatment Outcome