Molecular imaging metrics to evaluate response to preclinical therapeutic regimens

Abstract

Molecular imaging comprises a range of techniques, spanning not only several imaging modalities but also many disease states and organ sites. While advances in new technology platforms have enabled a deeper understanding of the cellular and molecular basis of malignancy, reliable non-invasive imaging metrics remain an important tool for both diagnostics and patient management. Furthermore, the non- invasive nature of molecular imaging can overcome shortcomings associated with traditional biological approaches and provide valuable information relevant to patient care. Integration of information from multiple imaging techniques has the potential to provide a more comprehensive understanding of specific tumor characteristics, tumor status, and treatment response.

Figure 1

Assessment of (18F)FLT uptake in vehicle- and trastuzumab-treated BT474 human breast cancer xenografts. (18F)FLT-PET images of vehicle-treated (A) and trastuzumab-treated (B) BT474 tumor-bearing mice illustrating significantly reduced (18F)FLT uptake in the tumor of a trastuzumab treated mouse. No change in BT474 tumor (18F)FLT uptake was observed following vehicle treatment (C), yet a statistically significant decrease was observed across a cohort of trastuzumab-treated mice (D). All images and data shown were collected after 1 wk of vehicle or trastuzumab therapy. Reproduced with permission from (23), modified.

Figure 2

Rapamycin synergizes with trastuzumab to decrease tumor viability and glucose metabolism. Tumor-bearing mice were baseline imaged by positron emission tomography for (18F)FDG uptake, randomized to trastuzumab, rapamycin, or the combination (n = 5–6 per group) treatment on days 0, 2, 4, and 6, and reimaged on day 7 (n = 4–5 per group). Images from a representative mouse show (18F)FDG uptake pretreatment and post-treatment. Plot of the % change in (18F)FDG uptake at day 7 compared with baseline is shown (right). Gray diamonds/circles are indicative of two tumors within the same mouse. #, P = 0.0586, Mann-Whitney U test between treatment groups. Reproduced with permission from (27), modified.

Figure 3

MicroPET/CT imaging of human tumor xenografts before and after gefitinib treatment. Tumor-bearing mice were subjected to a microPET/CT scan before (baseline scans) and after two oral doses of gefitinib (70mg/kg/d). Arrows denote the location of tumors. Reproduced with permission from (28), modified.

Figure 4

(A) representative fluorescence image of a mouse bearing a 4T1 xenograft tumor on the right hind limb. Image was collected 24 h after administration of NIR800-aVEGFR2ab demonstrating significant accumulation of the imaging probe within the tumor region. Single channel unmixed image of NIR800-aVEGFR2ab uptake (left) as well as multichannel fluorescence composite image of autofluorescence (white) and NIR800-aVEGFR2ab uptake (red) are shown (right). (B) representative fluorescence image of a mouse bearing a similar 4T1 xenograft tumor 24 h after administration of non-specific NIR800-IgG probe. Retention of the nonspecific probe was not observed within the tumor region. Single channel unmixed image of NIR800-IgG uptake (left) as well as composite image of autofluorescence (white) and NIR800-IgG (red) are shown (right). (C) quantified fluorescence intensity of the tumor region normalized to contralateral flank for mice injected with the NIR800-aVEGFR2ab probe (n=20) and the nonspecific NIR800-IgG probe (n=6). Reproduced with permission from (64).

Figure 5

Accumulation of NIR700-AnnexinV is enhanced in MMTV/HER2 tumors responding to trastuzumab. NIR700-AnnexinV was administered i.v., and mice were serially imaged up to 44 h before and after treatments with trastuzumab or vehicle (PBS). Representative images from responding (A) and nonresponding (B) MMTV/HER2 tumor-bearing mice (24h images shown). Significant accumulation of NIR700-AnnexinV was observed within the responsive tumor after 2 wk of trastuzumab treatment (A), whereas the nonresponsive tumor does not show significant NIR700-AnnexinV uptake (B). T, tumor; K, kidney; M, reference muscle. Reproduced with permission from (23).

Figure 6

ADC maps before (A) and after (B) treatment of DiFi xenograft tumor with C225. ADC values in tumor are lower than surrounding normal tissues prior to C225 treatment; “T” = tumor. Weighted mean ADC pre-treatment = 9.93e−04 mm²/s. Following C225, increased ADC is observed in the tumor. Weighted mean ADC post-treatment = 1.2e−03 mm²/s.