Leveraging Technology to Improve the Standard of Care (Technology Branch)
Technology focused research has the overall goal of leveraging technologic advances to improve the precision of radiotherapy. General objectives include investigating new algorithms, refining target delineation, developing advanced imaging techniques, and facilitating clinical trials. Projects currently underway at this time include those related to proton therapy, imaging, and quality assurance and control.
- Optimize proton therapy delivery through standardization of clinical simulation, dosimetric planning, treatment verification, and real-time adaptive planning procedures
- Minimize the uncertainties that could limit the effectiveness of current state-of-the-art proton therapy through robust planning and knowledge-based treatment planning
- Quantify the biological effectiveness of proton therapy by using novel high-throughput methods and both traditional and novel biological endpoints
- Facilitate randomized clinical trials to investigate clinical outcomes of proton therapy
- Perform secondary analyses comparing the outcomes from ongoing proton trials with those from conventional photon-based treatment
- Investigate advanced imaging techniques and new imaging registration algorithms as a way of enhancing and standardizing the delineation of relevant tumor targets and normal tissue structures
- Identify tumor and normal tissue imaging biomarkers associated with radiation response through the use of advanced imaging techniques
- Investigate the consequences of inter- and intra-fractional variations in anatomic, biological, and functional characteristics of tumors and normal tissues, and develop and evaluate strategies to mitigate their consequences
- Develop clinical protocols that permit real-time therapeutic approaches by coupling in-room imaging with treatment planning and delivery techniques
Quality Assessment and Quality Control
- Develop quality assurance methods for radiation therapy delivery that account for tumor motion and anatomic changes
- Establish quality control procedures for the various process components of radiation therapy through infrastructure for data organization and artificial intelligence for data mining
- Verify dose distributions on-line and/or off-line by developing new dosimetric detectors, for use with in vitro and in vivo dosimetry technologies
A major focus in this theme is the use of MRI (eventually with a dedicated MR simulator) to define radiographic predictors of radiation treatment response. Through a master research agreement with Elekta Corp., several investigator-initiated clinical trials are in progress to evaluate novel imaging parameters in esophageal, rectal, head and neck, breast, and prostate cancer. Once reliable biomarkers of radioresponse are identified and validated, image-guided interventions can then be proposed, including whole-tumor or focal radiation boosts to areas of radioresistance, or biologic modifiers of therapy. In addition to these MRI-related activities, the Center’s cumulative expertise in spatially accurate deformable image-registration, a Bayesian framework for this, quantitative extraction of imaging features, and imaging informatics for clinical trials will advance research activities in this theme.
Mechanisms of Cell Responses to Radiation Therapy (Biological Studies Branch)
Research within the Biological Studies Branch focuses on using clinical samples and outcomes to inform preclinical investigations for development of biomarkers and combination therapies that could significantly improve efficacy of radiation therapy.
Cell Line Bank
- Generate pairs of isogenic cell lines with differing radiosensitivities by serial low-dose irradiation
- Define unifying or distinct molecular signatures of radioresistance using these paired cell lines
- Establish panels of cell lines with specific alterations in radiation-related proteins using CRISPR-cas9 technology
Clinical Biospecimen Analysis
- Identify, locate, and assess highly informative banked tissues from patients who received preoperative radiotherapy and did or did not experience a complete pathologic response
- Analyze post-radiation residual tumor samples from archived and prospectively collected tissues stratified by the presence or absence of subsequent local failure in the irradiated area
- Utilize new technologies such as next-generation sequencing to perform the analyses listed above
- Identify and prioritize druggable pathways from the analyses listed above to guide preclinical studies
- Use quantitative imaging to correlate tissue and blood-based biomarkers with imaging parameters to generate integrated radiogenomic signatures of radioresponse
- Perform high-throughput screening to identify therapeutic agents that sensitize numerous tumor cell types to radiation
- Investigate new pharmacologic agents targeting specific molecular pathways as potential synergistic treatment approaches to enhance radiation therapy
- Repurpose currently approved drugs as potential radiosensitizers
- Expand development of strategies to protect normal tissues from the side effects of radiation
The quest for translation of preclinical findings to clinical applications has fueled a new cadre of clinical trials. One trial is BATTLE XRT, which evaluates ARQ 197 (a c-Met inhibitor) and concurrent chemoradiation, with or without erlotinib, for lung cancer and includes extensive exploratory analysis of molecular markers, serum growth factor levels, and local control and survival. An evolving area of interest is the combination of immunotherapeutic agents with radiation therapy to improve not only local control but also potentially distant control. An investigator-initiated clinical trial of stereotactic radiation therapy for lung and liver metastases explores the role of immunotherapy in mediating a revived abscopal effect wherein treatment of one metastasis results in regression of other metastatic sites via radiation-induced in situ tumor auto-vaccination simultaneously with immune stimulation by checkpoint blockade. Another investigator-initiated clinical trial involves a nanotherapeutic formulation of paclitaxel as a radiosensitizer in pancreatic cancer.
Using Patient Outcomes to Improve Treatment (Human Health Services Branch)
- Research within the Human Health Services Branch assesses the effectiveness of various therapeutic interventions at the population level. The investigators utilize a Medicare database on breast cancer and SEER/Medicare databases for 20 disease sites to compare radiation treatment outcomes and costs on a national level
- Assess trends in the adoption of new radiation technologies in the clinic
- Analyze disparities in access to, acceptance of and utilization of radiation therapy in commonly encountered clinical scenarios and in end-of-life care
The health services group has produced numerous publications which have gone on to gain national attention in the press releases and have been featured in the Journal of the American Medical Association, Journal of the National Cancer Institute, and Journal of Clinical Oncology. These publications highlight the need to evaluate new technology thoroughly and also provided crucial information to women about breast cancer prevention and treatment. The Health Services branch aims to establish collaboration with the Department of Health Services Research and plans to maintain its focus on comparing effectiveness research and purchase additional national databases.
This group has ongoing funding from the National Cancer Institute, Varian Medical Systems, the American Society for Radiation Oncology (ASTRO), and the American Society for Clinical Oncology (ASCO). Our main areas of research focus on radiation therapy in palliative care, local-regional management of breast cancer, the comparative effectiveness of different treatment strategies for lung cancer, and physician and structural factors that contribute to management of prostate cancer. These investigations have produced numerous publications which have gone on to gain national attention in print and broadcast media and have been featured in the Journal of the American Medical Association, Journal of the National Cancer Institute, and Journal of Clinical Oncology.
Using Nanotechnology to Enhance the Effectiveness of Radiation Therapy
The Nanotechnology group of the CROR is new for 2014. Current efforts underway in this branch focus on building a team of experienced investigators to identify means to sensitize tumors to radiation therapy by using metallic nanoparticles to generate radiation dose-enhancement or hyperthermia, and developing nanoparticle-based molecular imaging probes to facilitate image-guided therapy. Studies of radiation dose-enhancement are exploring the use of tumor-specific bioconjugated gold nanoparticles and on-demand triggered release “payloads” of gold nanoparticles and siRNA.