Online monitoring and image-guided treatment of chemoresistant micrometastases

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DESCRIPTION (provided by applicant): Despite advances in cytoreductive surgery and chemotherapy, survival of metastatic epithelial ovarian cancer and pancreatic ductal adenocarcinoma remain dismal due in part to chemoresistant micrometastases undetectable by traditional imaging modalities. Both of these diseases involve peritoneal carcinomatosis, that is, extensive tumor studding of the peritoneal cavity and its resident organs. To address these "invisible" tumors, we introduce a series of cancer cell-targeted, activatable imaging and therapeutic agents integrated with cellular-resolution, multi-molecular fluorescence microendoscopy. We developed near-infrared photocytotoxic immunoconjugates (PICs) that target cell membrane molecules overexpressed by cancer cells, including the epidermal growth factor receptor, to serve as an imaging probe and combined photodynamic and anti-molecular therapeutic agent for tumor-targeted, activatable photoimmunotherapy (taPIT). The photodynamic and fluorescence components become de-quenched (activated) upon cancer cell binding, internalization and processing. This strategy overcomes off-target phototoxicity-including bowel phototoxicity-the major clinical obstacle for photoactivated treatments in complex sites such as the pelvic cavity. This proposal builds on our prior work that shows the PIC binds ovarian micrometastases with 93% sensitivity and 93% specificity in vivo, enabling accurate recognition of tumors as small as 30 �m and selective destruction of micrometastases. We propose to further develop this platform to specifically address chemoresistant micrometastases, which represent a critical niche in cancer therapy. Current clinical imaging technologies cannot resolve microscopic tumor deposits left behind by surgery and chemotherapy, and there are limited treatment options for patients with recurrent, chemoresistant tumors. We anticipate that this new paradigm for microendoscopy-guided taPIT will complement current treatment modalities for patients with advanced-stage disease and those receiving salvage therapies.