Multiplexed and dynamically targeted photoimmunotherapy of heterogeneous, chemoresistant micrometastases guided by online in vivo optical imaging of cell-surface biomarkers - PROJECT SUMMARY
Despite advances in surgery, chemotherapy and targeted therapies, survival of metastatic epithelial ovarian
cancer remains dismal due in part to tumor heterogeneity and residual microscopic disease undetectable by
traditional imaging modalities. This malignancy involves peritoneal carcinomatosis at advanced stages; that is,
extensive tumor studding of the pelvic cavity and its resident organs. To address these “invisible” tumors, we
introduce a series of molecular-targeted and cell-activatable imaging and therapeutic agents integrated with a
newly developed miniaturized microscope for multiplexed molecular imaging in vivo—a cellular-resolution
hyperspectral fluorescence microendoscope—that uniquely enable visualization of microscopic deposits of
tumor cells deep inside the body. The multiplexed biomarker imaging feature is motivated by the critical need
to quantitatively monitor cancer cell phenotypes salient to treatment resistance and escape (e.g., cancer stem
cells are defined by multiple cell-surface biomarkers). In parallel, we have also developed near-infrared
photocytotoxic immunoconjugates (PICs) that target cell membrane molecules overexpressed by cancer cells,
including the epidermal growth factor receptor (EGFR), to create a combined photodynamic and receptor
antagonist therapeutic agent for tumor-targeted, activatable photoimmunotherapy (taPIT). The photodynamic
and fluorescence components become de-quenched (activated) upon cancer cell binding, cellular
internalization and lysosomal antibody proteolysis. This strategy overcomes off-target phototoxicity, including
bowel phototoxicity, the major clinical obstacle for photoactivated treatments in complex sites such as the
pelvic cavity. Here, we build on our prior work that shows the PIC is activated within ovarian micrometastases
with 93% sensitivity and 93% specificity in vivo, in a xenograft mouse model using EGFR overexpressing
human epithelial ovarian cancer cells, enabling accurate recognition of tumors as small as 30 μm and selective
destruction of disseminated peritoneal micrometastases. We propose to further develop this platform to
address tumor heterogeneity and chemoresistant phenotypes lurking within residual tumor deposits, which
represents 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, opening new avenues for personalized medicine. The new capabilities will be applied to
guide dynamically targeted taPIT adaptive to phenotype evolution in response to therapy and for monitoring
treatment response of microscopic residual disease.
