Optical imaging with her2-targeted affibody molecules can monitor hsp90 treatment response in a breast cancer xenograft mouse model.

Abstract

PURPOSE:

To determine whether optical imaging can be used for in vivo therapy response monitoring as an alternative to radionuclide techniques. For this, we evaluated the known Her2 response to 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG) treatment, an Hsp90 inhibitor.

EXPERIMENTAL DESIGN:

After in vitro 17-DMAG treatment response evaluation of MCF7 parental cells and 2 HER2-transfected clones (clone A medium, B high Her2 expression), we established human breast cancer xenografts in nude mice (only parental and clone B) for in vivo evaluation. Mice received 120 mg/kg of 17-DMAG in 4 doses at 12-hour intervals intraperitonially (n = 14) or PBS as carrier control (n = 9). Optical images were obtained both pretreatment (day 0) and posttreatment (day 3, 6, and 9), always 5 hours postinjection of 500 pmol of anti-Her2 Affibody-AlexaFluor680 via tail vein (with preinjection background subtraction). Days 3 and 9 in vivo optical imaging signal was further correlated with ex vivo Her2 levels by Western blot after sacrifice.

RESULTS:

Her2 expression decreased with 17-DMAG dose in vitro. In vivo optical imaging signal was reduced by 22.5% in clone B (P = 0.003) and by 9% in MCF7 parental tumors (P = 0.23) 3 days after 17-DMAG treatment; optical imaging signal recovered in both tumor types at days 6 to 9. In the carrier group, no signal reduction was observed. Pearson correlation of in vivo optical imaging signal with ex vivo Her2 levels ranged from 0.73 to 0.89.

CONCLUSIONS:

Optical imaging with an affibody can be used to noninvasively monitor changes in Her2 expression in vivo as a response to treatment with an Hsp90 inhibitor, with results similar to response measurements in positron emission tomography imaging studies.

• Authors: Stephanie M W Y van de Ven, Sjoerd G Elias, Carmel T Chan, Zheng Miao, Zhen Cheng, Abhijit De, Sanjiv S Gambhir
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 4 Pg. 1073-81 (Feb 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22235098 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Recombinant Fusion Proteins
• affibody (ZHER2-342)2
• 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
• Receptor, ErbB-2

Topics

• Animals
• Benzoquinones (administration & dosage, pharmacology)
• Breast Neoplasms (diagnosis, drug therapy, genetics)
• Down-Regulation (drug effects)
• Female
• Gene Expression
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Lactams, Macrocyclic (administration & dosage, pharmacology)
• Mice
• Mice, Nude
• Molecular Imaging (methods)
• Receptor, ErbB-2 (genetics, metabolism)
• Recombinant Fusion Proteins
• Xenograft Model Antitumor Assays