Funding Sources / Paganetti team
NIH grant support
- P01 CA241508 (co-PI: Paganetti)
- U24 CA215123 (site PI: Paganetti)
- R01 CA187003 (PI: Schuemann)
- R01 CA229178 (PI: Paganetti)
- R01 CA248901 (PI: Paganetti)
- R01 EB031102 (PI: Paganetti)
- R01 CA266419 (PI: Schuemann)
- R21 CA248118 (PI: Grassberger)
- R21 CA252562 (PI: Schuemann)
- Contr. 2020A003480 (PI: Paganetti)
- K99 CA267560 (PI: Bertolet)
- Andrew L Warshaw (PI: Bertolet)
International research fellow grants
- Swiss National Science Found. (PI: Nesteruk)
- Swiss National Science Found. (PI: Nenoff)
- Korea Nuclear Int. Co. Found. (PI: Yoo)
- Loeffler Team Science Award (PI: Bertolet)
- Federal Share Income grant
Details about each funded project are given below
National Institute of Health (NIH)
The overall goals are (a) understanding relative clinical, biological and immuno-suppressive determinants of response to proton vs. photon therapy; (b) developing personalized response predictive models based on such determinants; and (c) applying individualized (as opposed to population-based) approaches for the selection of the optimum radiation modality for each patient and to enhance the therapeutic potential with IMRT and IMPT dose distributions tailored to an individual patient’s baseline and tumor characteristics. These goals will be achieved in three synergistic projects. Project 1: Understanding Normal Tissue Toxicity to Identify Patients Most Likely to Benefit from Proton vs. Photon Therapy; Project 2: Radiation-Induced Lymphopenia: Understanding, Predictive Modeling and Developing Photon and Proton-Based Mitigation Strategies; and Project 3: Investigating Enhanced Sensitivity of Tumors to Proton Beam Therapy: Mechanisms and Biomarkers. The projects are highly integrated in that treatment modality selection and dose distribution optimization to maximally enhance the therapeutic ratio must consider and balance normal tissue complications (Project 1), radiation-induced immuno-suppression (Project 2) and tumor response based on genotypic factors (Project 3), which cannot be accomplished by any one project alone.
While adaptive therapy has been studied before, none of the previous studies deals with the unique challenges (range uncertainties) and unique capabilities (beamlet optimization and prompt gamma imaging) of proton therapy. This proposal will for the first time address these aspects by developing innovative hardware and software methodologies. We envision treatment planning and delivery to be fully adaptive in terms of intra- fractional changes in patient geometry. This proposal aims at predicting the dose distribution (or a surrogate thereof) in the patient immediately prior to treatment delivery and correct for any discrepancies between the measured and intended dose in less than 2 minutes. This will enable us to deliver (proton) radiation therapy in an adaptive setting and much reduced target volume margins (2mm isotropic plus 2mm range margin in proton therapy in the beam direction) daily while the patient is positioned on the treatment table. We propose to achieve this goal by simultaneously developing fast hardware and software tools that take advantage of in-room prompt gamma and cone-beam CT imaging in combination with fast dose calculation. We will combine this technology with a novel framework on beamlet adaptation. While some of our methods will improve photon therapy as well, we will focus on proton therapy because it offers unique opportunities to dose verification in vivo as well as unique challenges due to range uncertainties. Our methodology will be made available to the entire proton therapy community.
This proposal will develop methods to quantify the interaction of radiation with the immune system, particularly the blood (i.e., circulating lymphocytes). We envision that future treatment planning in radiation oncology will treat lymphatic nodes and the blood as organs at risk and include them in the treatment optimization process so as to influence the level at which the radiation treatment impacts the immune system of the patient. During radiation therapy, depletion of circulating lymphocytes originates mainly from (1) immediate cell killing during irradiation of blood vessels, and thus circulating lymphocytes, within the treatment field and (2) to a lesser extent, the radiation dose to lymphocytes residing within lymphoid organs that can mobilize their lymphocyte population upon systemic depletion. There are currently no whole-body computational phantoms available that can facilitate the calculation of blood or lymphocyte dose-volume histograms. However, this tool is a prerequisite to the use of bio-mathematical models for clinical trial design. The phantoms to be developed in this study will be the first to fill this urgent need for the radiation therapy and research communities. In addition to the overall innovative nature of this project, several of our methods are novel and have never been employed in our field: • The first use of tetrahedral mesh structures to model blood vessels (SA1) • The first implementation of a whole-body compartment model for blood flow (SA2) • The first four-dimensional modeling of blood flow using vasculature structures (SA3) • The first model of the mouse vasculature for pre-clinical studies (SA4)
NIBIB R01 EB031102 Constrained Disentanglement (CODE) Network for CT Metal Artifact Reduction in Radiation Therapy
A majority of cancer patients receive radiation therapy as a critical part of their treatment, and many of these patients have metal objects leading to metal-induced CT artifacts. Metal artifacts compromise or preclude radiation therapy in an estimated 15% of all radiation therapy patients. Our overall goal is to eliminate CT metal artifacts in general and improve RT in particular using an integrated deep learning solution.
NCI R21 CA252562 Understanding the importance of dose-rate variations for patient treatments in FLASH and conventional radiation therapy
Radiation therapy has been an important component in the treatment of cancer for many decades. While the parameters of tumor control have been relatively well understood, normal tissue complication probabilities (NTCPs) are often only thought of as constraining factors in the design of a treatment regimen. However, with continuously improving treatments of primary lesions, NTCP and their impact on the quality of life have moved into the focus of research. One of the most prominent methods reported to spare healthy tissue is FLASH radiation therapy, i.e. ultrafast (>40 Gy/s) irradiations, which reportedly results in incredible tissue sparing effects without compromising efficacy for tumor cure. Conversely, very low dose-rate irradiations have also been reported to offer protective features. Together, these experiments suggest that the current clinical routine, treating patients with a medium dose-rate of ~2 Gy/min, could in fact be the least favorable when considering healthy tissue side effects. In clinical practice, patients are treated with a variety of radiation treatment modalities. While the resulting target doses are similar across modalities, the dose delivered to the normal tissue and the time structure of the delivery can vary significantly. Despite the range of dose-rates across treatment plans, the biological effect is estimated only based on the total dose received. We hypothesize that dose-rate plays an important role in the outcome of radiation therapy that can be exploited for specific treatment scenarios. For extreme cases such as FLASH therapy, averaged dose-rates do not capture the relevant time structures adequately. We will apply Monte Carlo simulations to determine time structures from the clinical scale of minutes (spot scanning / gantry rotation time) to nanoseconds (intra-spot delivery time) and assess potential effects on healthy tissue sparing that would improve the quality of life for radiation therapy patients.
NCI contract 2020A003480 Monte Carlo for Pediatric Proton Epidemiology
Andrew L. Warshaw, M.D., Institute for Pancreatic Cancer Research
Radiobiological modeling of alpha-particle radiopharmaceutical therapy for pancreatic adenocarcinoma
Biological effects from α-particles in RPT are conditioned by the geometry of the cells irradiated, the uptake and binding specificity of the radioconjugate, and the physical properties of the radionuclide. We will model in-silico the experiments carried out with 212Pb-labeled conjugates, simulating the effects of variable geometries and binding in TOPAS-nBio.Tumors are composed of heterogeneous cells in irregular structures so that an ideal geometrical representation may be not possible. Therefore, a generalization from the cell-scale results in SA1 will be made, assessing the effect of heterogeneous distribution uptake among tumor cells and the effect of irregular growth of tumors. We will explore how to transition from cell-scale endpoints, such as damage to DNA, to tumor-scale endpoints, such as tumor growth or tumor control probability.