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. 2015 Oct 15;75(20):4283-91.
doi: 10.1158/0008-5472.CAN-15-0471.

Preclinical Validation of the Utility of BLZ-100 in Providing Fluorescence Contrast for Imaging Spontaneous Solid Tumors

Janean Fidel  1 , Katie C Kennedy  1 , William S Dernell  1 , Stacey Hansen  2 , Valorie Wiss  2 , Mark R Stroud  2 , Joshua I Molho  3 , Sue E Knoblaugh  4 , Jeffrey Meganck  3 , James M Olson  4 , Brad Rice  3 , Julia Parrish-Novak  5
Affiliations

Preclinical Validation of the Utility of BLZ-100 in Providing Fluorescence Contrast for Imaging Spontaneous Solid Tumors

Janean Fidel et al. Cancer Res. .

Abstract

There is a need in surgical oncology for contrast agents that can enable real-time intraoperative visualization of solid tumors that can enable complete resections while sparing normal surrounding tissues. The Tumor Paint agent BLZ-100 is a peptide-fluorophore conjugate that can specifically bind solid tumors and fluoresce in the near-infrared range, minimizing light scatter and signal attenuation. In this study, we provide a preclinical proof of concept for use of this imaging contrast agent as administered before surgery to dogs with a variety of naturally occurring spontaneous tumors. Imaging was performed on excised tissues as well as intraoperatively in a subset of cases. Actionable contrast was achieved between tumor tissue and surrounding normal tissues in adenocarcinomas, squamous cell carcinomas, mast cell tumors, and soft tissue sarcomas. Subcutaneous soft tissue sarcomas were labeled with the highest fluorescence intensity and greatest tumor-to-background signal ratio. Our results establish a foundation that rationalizes clinical studies in humans with soft tissue sarcoma, an indication with a notably high unmet need.

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Figures

Figure 1
Figure 1
Fluorescence intensity analysis in tumors. (A) Total signal in ROIs from Odyssey scans of gross tumors, grouped by tumor type. ROIs sizes and scan settings were constant across the data set. Linear regression was performed for the whole set, and for the dose groups below and above 0.85 mg/m2. Significant correlation between dose and intensity was seen only in the low dose group (R2 = 0.6, P = 0.02), suggesting that maximal uptake into tumors is reached at ~0.8 mg/m2. (B) Odyssey fluorescence scan and (C) H&E stain of tissue sections from patient 12. Comparison with histology was used to verify regions of tumor and non-tumor in tissue samples.
Figure 2
Figure 2
Imaging and ROI analysis of ex vivo tumor and normal tissues. Pseudocolored heat maps of Odyssey images (top), photographs (bottom left,) and H&E (bottom right) are shown for each representative dog. ROIs were chosen within gross tumor (black) and gross normal (yellow) tissue samples. (A) Patient 25 had a sarcoma on the eye lid. TBR is 4.5 compared to immediately adjacent normal fat tissue. (B) Patient 12 had a soft tissue sarcoma in the right front axillary region. TBR is 8.9 compared to normal skin. (C) Patient 23 had a squamous cell carcinoma on the tail. TBR is 13 compared to uninvolved skin. (D) Patient 13 had a subcutaneous hemangiopericytoma, a type of soft tissue sarcoma. TBR is 79 compared to adjacent fat. (E) Patient 17 had a fibrosarcoma in the jaw. TBR is <1.0 compared to a section of lower lip.
Figure 3
Figure 3
Intraoperative NIR imaging system. (A) Prototype instrument used in this study. (B) Commercial version of the instrument, Solaris.
Figure 4
Figure 4
Intraoperative imaging of a soft tissue sarcoma (patient 19). (A) White light preoperative image of gross tumor showing ulcerated and grossly swollen peritumoral skin. (B) NIR image (40 msec integration time) of tumor in situ. (C) Plot of fluorescence intensity along the line drawn through the image in panel B. (D) NIR image of excised tumor, with instrument settings adjusted to maximize contrast in order to highlight the variable appearance of the tumor. This tumor was classified as grade II soft tissue sarcoma with ~50% necrosis.
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