Multiparameter noninvasive assessment of treatment susceptibility, drug target inhibition and tumor response guides cancer treatment.
New cancer therapies are increasingly molecular-pathway specific. The evaluation of these novel therapies would be greatly facilitated by the development of noninvasive methods to assess multiple tumor cellular and molecular parameters. Using fluorescent probes specific for HER2/neu (AF750-trastuzumab) and apoptosis (Cy5.5-Annexin), we demonstrate a multichannel near infrared molecular imaging approach that yields accurate and early assessment of treatment susceptibility, drug target inhibition and tumor response during HER2-targeted therapy of orthotopic human mammary carcinomas in mice with trastuzumab (Herceptin). This combined approach detects both partial treatment response (tumor growth inhibition without regression) as well as therapeutic resistance before alterations in tumor growth are apparent. Partially responsive tumors exhibit increased Annexin signal when trastuzumab is combined with a cytotoxic agent (paclitaxel), which predicts subsequent tumor regression and suggests that imaging can guide therapy optimization. This multiparametric imaging approach has great potential in the clinical setting for determining patient eligibility, adequate drug dosing and early biological response of molecularly-targeted cancer therapies.
Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Michael S
MS
Gee
Rabi
R
Upadhyay
Henry
H
Bergquist
Ralph
R
Weissleder
Lee
L
Josephson
Umar
U
Mahmood
D000818:Animals; D017302:Annexins; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy; D045744:Cell Line, Tumor; D042241:Early Diagnosis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000175:diagnosis / Q000188:drug therapy; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000737:chemistry / Q000175:diagnosis* / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011237:Predictive Value of Tests; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D019265:Spectroscopy, Near-Infrared; D000068878:Trastuzumab; D015854:Up-Regulation
D017302:Annexins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab