How do you fight an enemy you cannot see? Despite the amazing progress over the past decades in detecting and treating cancer, an outstanding problem in the field of oncology is the battle against microscopic metastatic disease. The vast majority of cancer-related deaths are associated not with the primary tumor itself, but with the multitude of disseminated metastatic lesions that occur throughout the body. These lesions are often far too small and widespread to detect and resect, and in many cases ultimately become resistant to therapeutic intervention. How these lesions resist treatment is not well understood, as we are currently unable to visualize treatment response on the microscale in vivo.
A major cause of treatment resistance in all cancers is hypoxia, which is caused by cellular oxygen deprivation. Hypoxia triggers an array of built-in cellular defense mechanisms, allowing hypoxic tumor cells to resist many potent therapies. Front-line therapies such as carboplatin and paclitaxel become ineffective in hypoxic environments, with paclitaxel demonstrated to be over 100 times less effective under hypoxic conditions. Radiation therapy and most PDT regimens require O2 for their cytotoxic effects, and thus lose efficacy in hypoxic environments. Importantly, hypoxia is highly heterogeneous on the microscale, leading to a complex and mostly unknown landscape of treatment response. As this heterogeneity is difficult to visualize in disseminated metastatic disease in situ, little is known about the distribution of hypoxia and how this distribution affects therapeutic efficacy.
We seek to overcome these challenges through an innovative imaging approach to build a comprehensive, cellular-level picture of treatment response and resistance in disseminated metastatic cancer. By mapping out therapeutic response using multimodal imaging, models of metastatic cancer, and in vivo imaging tools, our reseach will enable explorations of the currently unknown microscale relationships between hypoxia and treatment response on a cell-to-cell, nodule-to-nodule basis in disseminated disease. At the same time, we are using this critical microscopic information to build new oxygen-independent therapeutic regimens capable of targeting hypoxic microenvironments to stop treatment-resistant disease before it can start.
1. Development and application of molecular oxygen probes for deep tissue, cellular-level real-time oxygen imaging. We are currently synthesizing new polymer-based oxygen sensors that are rapidly taken up into cancer cells, allowing for both rapid and long-term pO2 imaging.
2. Creation of new photodynamic therapy regimens for the effective treatment of hypoxic, therapeutically-resistant tumor environments. We are currently focusing our efforts developing and applying “Type-I” photosensitizers that home into and retain their efficacy even in severely hypoxic tumor environments.
3. High Throughput, High-Content screening of patient-derived tumors for personalized chemotherapuetic planning. We are developing a microscopy platform focused on visualizing the therapeutic response of large number of three-dimensional tumor nodules utilizing multimodality imaging. We are currently building a new screening system utilizing confocal and multiphoton microscopies, CARS/SRS microscopies, and optical coherence tomography to map out treatment resistance factors and optimize cancer treatment regimens.
4. Development of a fluorescence and optical coherence tomography miroendoscope for in situ visualization of therapeutic resistance and therapeutic response in patients with disseminated peritoneal lesions such as metastatic ovarian cancer.
Other projects are also under way – we are limited only by our drive and creativity!
Irene Kochevar, PhD
Jonathon Winograd, MD
Charles Lin, PhD