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.

Public Health Relevance

Small tumor deposits that escape surgical removal and chemotherapy represent a prominent source of cancer morbidity and mortality, and cannot be resolved using current clinical imaging technologies. The goal of this proposal is to develop a new paradigm for cancer therapy using optical imaging to detect residual, microscopic tumors and to guide photoimmunotherapy for treating chemoresistant micrometastases while also re- sensitizing them to chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K22)
Project #
1K22CA181611-01A1
Application #
8821877
Study Section
Subcommittee G - Education (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2015-09-23
Project End
2018-08-31
Budget Start
2015-09-23
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$186,276
Indirect Cost
$11,576
Name
Northeastern University
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115