Research projects currently underway in the BIRTLab, include:
- Development of a 3D optical tomography-guided system for pre-clinical radiation therapy research in tumor localization, radiation guidance, and treatment assessment
- Investigation of image-guided ultra-high-dose rate (FLASH) radiation therapy for new cancer treatment paradigm
- In vivo tumor cell tracking and facilitating therapeutic development
Multimodal Quantitative Imaging-Guided System for Pre-Clinical Radiation Research
Unmet needs in current pre-clinical radiation therapy (RT) research include the following: 1) knowing the target’s shape is fundamental for guiding radiation because over-irradiating normal tissue or underdosing tumors can lead to undesired experimental uncertainties; and 2) functional imaging-guided small animal irradiators are not readily available to perform biology-guided RT methods to support translational studies. Moreover, functional imaging is an important technology in pre-clinical research, thus allowing treatment response to be robustly quantified to strengthen scientific findings.
Cone-beam CT/CBCT-guided small animal irradiator has been widely used to test radiobiological hypotheses to closely mimic human treatment. However, it is less adept at localizing soft tissue targets that grow in a low-image contrast environment; also, it does not provide functional information. In contrast, bioluminescence and fluorescence imaging offer strong image contrast and functional information, so they are attractive solutions for soft-tissue imaging guidance. However, 2D optical imaging commonly used on animal surfaces is inadequate to guide irradiation because optical transportation from an internal optical target is highly susceptible to the effects of the irregular torso and tissue optical properties.
Recognizing these limitations has led us to integrate 3D bioluminescence tomography (BLT) and fluorescence tomography (FT) with small animal irradiators. In optical tomography, we use a forward model of light propagation through the tissue to the animal skin surface, in conjunction with an optimization algorithm, to reconstruct the underlying 3D source distribution.
Novel In Vivo Research Platform for FLASH Radiation Therapy
Radiation therapy (RT) is a major pillar in cancer treatment, but tissue toxicity is a key adverse effect. Normal tissue protection in RT is currently achieved by fractionation and high-precision dose-delivery techniques. Despite major advances in treatment delivery to irradiate tumors and minimize normal tissue involvement (e.g. stereotactic RT), radiation-induced normal tissue toxicities still adversely affect treatment outcomes and patients’ quality of life.
FLASH-RT exploits a long-overlooked parameter dose rate to enable high curative doses to be delivered to tumors at extremely short periods at an ultra-high-dose rate (>40Gy/s) while protecting normal tissue. FLASH-RT was found to induce lower normal tissue toxicity than conventional dose-rate irradiation, but to be just as effective in tumor control. Pre-clinical evidence has supported its effectiveness for potential use in clinics.
However, the mechanism underlying FLASH’s effect is still unknown and more work is needed for its clinical translation. A few hypotheses related to tissue oxygenation have been proposed to explain the differential radiation response between normal tissue and tumor but have not been validated. Besides elucidating the mechanism, we need thorough studies for clinical translation, such as comparing clinic-relevant hypofractionated schemes with FLASH-RT to determine the therapeutic gain level for FLASH-RT. In this respect, biological in vivo studies are especially important. However, a major challenge for FLASH research is that very few systems can deliver ultra-high dose rate irradiation, while none of these systems are equipped with a proper image-guided system. Without an adequate image-guided system, precise in vivo FLASH studies will be difficult and underlying experimental uncertainties can lead to imprecise research conclusions. We believe that a small animal image-guided FLASH (SAIG-FLASH) research platform will enable accurate in vivo FLASH studies to facilitate clinical translation. We plan on developing this research system by 1) modifying a clinical linear accelerator (LINAC) to achieve ultra-high-dose rate irradiation and 2) developing an image-guided research system for FLASH-RT.
We will integrate our advanced optical tomography with a CBCT system to provide optimal target localization and assessment capability for in vivo FLASH-RT. A theoretical O2 diffusion model and in vivo O2 measuring system will also be developed as unique research tools to study the FLASH mechanism.
FLASH-RT is a paradigm-shift modality that can change the way cancer patients are treated in the future. SAIG-FLASH is especially critical to enable accurate in vivo studies that will facilitate clinical translation.
In Vivo Glioblastoma Cell Tracking with Optical Tomography
The development of highly sensitive bioluminescence reporters, e.g., Akaluc and Akalumine-HCL, enables cell tracking in vivo. Through our advanced bioluminescence tomography (BLT) system, we are investigating the potential combination of BLT with the Akaluc reporter to investigate glioblastoma (GBM) cell migration. GBM is an aggressive type of cancer that develops in the brain. Patients typically survive 12-15 months from diagnosis, with fewer than 3 to 7% who survive longer than 5 years. Because of their diffuse nature, GBM stem cells are difficult to be completely removed by surgery and may also cause resistance to conventional treatments and high recurrence rates. Therefore, understanding how the GBM stem cells migrate is a key step toward developing therapeutic intervention. We will integrate BLT with a high-resolution cone beam CT system and utilize the new BL reporter to enable in vivo GBM cell tracking.