Michael Stanley Gee MD,PhD, Presenter: Nothing to Disclose

Rabi Upadhyay, Abstract Co-Author: Nothing to Disclose

Henry Bergquist, Abstract Co-Author: Nothing to Disclose

Lee Josephson PhD, Abstract Co-Author: Nothing to Disclose

Ralph Weissleder MD, PhD, Abstract Co-Author: Stockholder, VisEn Medical, Inc Consultant, Siemens AG

Umar Mahmood MD, Abstract Co-Author: Research Consultant, VisEn Medical, Inc, Woburn, MA Stockholder, VisEn Medical, Inc, Woburn, MA

To determine if multichannel near-infrared optical imaging can assess treatment susceptibility, therapeutic HER2 inhibition and early tumor response during trastuzumab (Herceptin) treatment of breast cancer.

Optical probes were generated by conjugating Herceptin and Annexin V with near infrared fluorochromes. BT474 and SKBR3 HER2-overexpressing breast cancer lines, HER2-normal MCF7 cells and non-HER2 expressing 9L cells were used. Tumors were established by mammary implantation into nude mice, and tumors were imaged for HER2 and apoptosis before and following Herceptin treatment. Intravital laser scanning microscopy was also performed on tumors in dorsal window chambers. Apoptosis and tumor cell proliferation were assessed by flow cytometric and histologic techniques.

HER2 probe shows increased binding to HER2-overexpressing tumors compared with HER2 normal tumors in vitro and in vivo, with binding correlating with Herceptin susceptibility. Herceptin treatment of HER2-overexpressing tumors reduces HER2 probe binding and inhibits tumor growth. Multichannel imaging detects HER2 inhibition and tumor apoptosis in treated SKBR3 tumors. No increase in Annexin signal despite HER2 inhibition is observed following treatment of SKBR3 R1 tumors, which maintain HER2 overexpression but have downstream alterations conferring Herceptin resistance, or BT474 tumors, which undergo growth arrest but not apoptosis in response to Herceptin. Combination therapy of BT474 tumors with Herceptin and paclitaxel, which causes apoptosis in vitro, increases tumor Annexin binding and causes tumor regression. Histology confirms the Annexin probe-binding tumor regions correspond to apoptotic areas.

Multichannel optical imaging provides accurate assessment of treatment susceptibility, drug target inhibition and early tumor response during Herceptin treatment of breast cancer. Tumor response can be determined before tumor growth effects are apparent, providing an early opportunity to modify treatment in order to optimize response.

This multiparametric imaging approach has great potential for evaluating new and existing cancer therapies, which are increasingly disease and molecular pathway specific.

Gee, M, Upadhyay, R, Bergquist, H, Josephson, L, Weissleder, R, Mahmood, U, Simultaneous Noninvasive Assessment of Drug Target Inhibition and Early Treatment Response during Cancer Therapy.  Radiological Society of North America 2006 Scientific Assembly and Annual Meeting, November 26 - December 1, 2006 ,Chicago IL. http://archive.rsna.org/2006/4429515.html