Browsing by Author "Whitley, Melodi Javid"

Local recurrence is a common cause of treatment failure for patients with solid tumors. Intra-operative detection and selective ablation of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of re-excision, and tailor adjuvant therapy, all of which may contribute to improved disease control. Here, we use a protease–activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human Phase I clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells and residual fluorescence detected within the tumor bed predicted local recurrence. In fifteen patients with STS or breast cancer, intravenous injection of LUM015 prior to surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissue. Comparison of LUM015 biodistribution and metabolism in mouse and human subjects revealed similar pharmacokinetic profiles for this PEGylated imaging probe. The major fluorescent LUM015 metabolite was determined to be Cy5-Lysine. Tissue concentrations of LUM015 and its metabolites demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases to establish tumor to normal contrast. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor-specificity of protease-activated imaging probes, such as LUM015, is significantly dependent on both biodistribution and protease-activation. These results support future clinical trials of LUM015 in which intraoperative imaging of the tumor bed is compared to surgical margin histopathology.

I also describe a novel pulsed Nd:YAG laser ablation system that, when used in conjunction with LUM015, can identify and ablate cancer in vivo. Mice with primary STS were injected with the protease-activatable probe LUM015 to label tumors. Resected tissues from the mice were then imaged and treated with the laser using the paired fluorescence-imaging/ laser ablation device, generating ablation clefts with sub-millimeter precision and minimal underlying tissue damage. Laser ablation was guided by fluorescence to target tumor tissues, avoiding normal structures. The selective ablation of tumor implants in vivo improved recurrence-free survival after tumor resection. This prototype system has the potential to be modified so that it can be used during surgery to improve recurrence-free survival in patients with cancer.