Table of contents

The potential for local radiation therapy to elicit systemic (abscopal) anti-tumor immune responses has been receiving a significant amount of attention over the last decade. We recently developed a mathematical framework designed to simulate the systemic dissemination of activated T cells among multiple metastatic sites. This framework allowed the identification of non-intuitive patterns of T cell redistribution after localized therapy, and offered suggestions as to the optimal site to irradiate in order to maximize T cell redistribution entropy. Here, we evaluate the potential for this optimized T cell redistribution to increase the magnitude of an immune-mediated abscopal response, and describe the approach that would be necessary to validate this in the clinical setting. Primary challenges include the quantification of microenvironmental conditions at each site and evaluation of their influence on local T cell extravasation and expansion, efficient segmentation and delineation of multiple tumor sites on PET/CT scans, and thorough validation of model prediction performance.

In the tumour microenvironment, cancer cells directly interact with both the immune system and the stroma. It is firmly established that the immune system, historically believed to be a major part of the body's defence against tumour progression, can be reprogrammed by tumour cells to be ineffective, inactivated, or even acquire tumour promoting phenotypes. Likewise, stromal cells and extracellular matrix can also have pro- and anti-tumour properties. However, there is strong evidence that the stroma and immune system also directly interact, therefore creating a tripartite interaction that exists between cancer cells, immune cells and tumour stroma. This interaction contributes to the maintenance of a chronically inflamed tumour microenvironment with pro-tumorigenic immune phenotypes and facilitated metastatic dissemination. A comprehensive understanding of cancer in the context of dynamical interactions of the immune system and the tumour stroma is therefore required to truly understand the progression toward and past malignancy.

Initiation and development of cancer are usually accompanied by alterations in the cellular mechanical properties such as its stiffness and viscosity. Understanding the viscoelasticity of cancer cells can provide a better insight into the mechanics of the metastasis of cancer cells. Here, we use atomic force microscopy to compare the viscoelasticity of mammary epithelial cells with different metastatic potentials in their adherent and suspended states. We measure cell elasticity through the spatial mapping of Young's modulus using the force-indentation technique and cell viscosity using stress relaxation. The viscoelastic properties of cancer cells are associated with their malignancy and intrinsic cytoskeletal structures. Our results suggest that the Young's modulus of adherent cells inversely correlates to their malignancy and that the F-actin arrangement and intensity support the mechanical phenotype. For suspended cells, we observe that they exhibit lower elasticity than adhered cells due to the distribution of actin filaments at the cell cortex as well as reduced polymerization. Our viscosity results suggest that in both adhered and suspended cases, normal breast epithelial cells exhibit higher viscosity than that of cancer cells. Actin distribution and higher nucleus to cytoplasmic ratio in cancer cells are observed to be the two main factors in determining cell viscosity.

Applied radiofrequency (RF) energy induces hyperthermia in tissues, facilitating vascular perfusion This study explores the impact of RF radiation on the integrity of the luminal endothelium, and then predominately explores the impact of altering the conductivity of biologically-relevant solutions on RF-induced heating rates and cell death. The ability of cells to survive high sucrose (i.e. hyperosmotic conditions) to achieve lower conductivity as a mechanism for directing hyperthermia is evaluated.

RF radiation was generated using a capacitively-coupled radiofrequency system operating at 13.56 MHz. Temperatures were recorded using a FLIR SC 6000 infrared camera.

RF radiation reduced cell-to-cell connections among endothelial cells and altered cell morphology towards a more rounded appearance at temperatures reported to cause in vivo vessel deformation. Isotonic solutions containing high sucrose and low levels of NaCl displayed low conductivity and faster heating rates compared to high salt solutions. Heating rates were positively correlated with cell death. Addition of sucrose to serum similarly reduced conductivity and increased heating rates in a dose-dependent manner. Cellular proliferation was normal for cells grown in media supplemented with 125 mM sucrose for 24 h or for cells grown in 750 mM sucrose for 10 min followed by a 24 h recovery period in culture media.

Sucrose is known to form weak hydrogen bonds in fluids as opposed to ions, freeing water molecules to rotate in an oscillating field of electromagnetic radiation and contributing to heat induction. The ability of cells to survive temporal exposures to hyperosmotic (i.e. elevated sucrose) conditions creates an opportunity to use sucrose or other saccharides to selectively elevate heating in specific tissues upon exposure to a radiofrequency field.

Lung cancer is often classified by the presence of oncogenic drivers, such as epidermal growth factor receptor (EGFR), rather than patterns of anatomical distribution. While metastatic spread may seem a random and unpredictable process, we explored the possibility of using its quantifiable nature as a measure of describing and comparing different subsets of disease. We constructed a database of 664 non-small cell lung cancer (NSCLC) patients treated at the University of Southern California Norris Comprehensive Cancer Center and the Los Angeles County Medical Center. Markov mathematical modeling was employed to assess metastatic sites in a spatiotemporal manner through every time point in progression of disease. Our findings identified a preferential pattern of primary lung disease progressing through lung metastases to the brain amongst EGFR mutated (EGFR^m) NSCLC patients, with exon 19 deletions or exon 21 L858R mutations, as compared to EGFR wild type (EGFR^wt). The brain was classified as an anatomic 'sponge', with a higher ratio of incoming to outgoing spread, for EGFR^m NSCLC. Bone metastases were more commonly identified in EGFR^wt patients. Our study supports a link between the anatomical and molecular characterization of metastatic lung cancer. Improved understanding of the differential biology that drives discordant patterns of anatomic spread, based on genotype specific profiling, has the potential to improve personalized oncologic care.

Surgery, radiation therapy and chemotherapy are the primary modes of therapeutic intervention in current clinical practice. The price often paid for effective treatment is the development of a secondary malignancy several decades after successful treatment of the primary tumor, as a result of the mutagenic effects of the initial cancer treatments on normal cells. In this work, we employ a biologically motivated mathematical model to estimate the radiation and chemotherapy-induced relative risks of thyroid malignancies in four childhood cancer study survivors (CCSS) data sets. A sensitivity analysis is performed on various chemotherapy treatment variables to evaluate their impact on second cancer risks. Furthermore, the predictions of radiation and chemotherapy-induced relative risks of secondary thyroid malignancies using the mathematical model are compared against four clinical datasets from the CCSS cohort. Moreover, the extracted average value of growth rate of premalignant cells is 0.8175 (d⁻¹) and the extracted chemotherapy-induced mutation rate is of the order of 10⁻¹⁰ (per unit of chemotherapeutic dose). In addition, our model predictions of sequential therapy induced carcinogenic risks are in line with the clinical data in secondary thyroid cancers. Our in silico risk predictions can provide insight into the impact of therapy sequencing on secondary cancer risks, while at the same time eliminating the primary tumor. These findings might potentially guide clinicians in developing optimal treatment regimens that minimize secondary cancer risks.

Intermittent treatment schedules have been proposed to improve the tolerance of drugs for cancer chemoprevention. However, determining a maximum tolerated dose, and the extent of the improvement, has been challenging experimentally and clinically. In order to determine the quantitative advantage of intermittent pulse treatment schedules for the chemoprevention of colon cancer we have used a computer model of human colon crypts calibrated with measurements of human biopsy specimens. In simulations, crypts were treated with an agent that increases the probability that cells, both normal and mutant, would be removed at the top of the crypt. Sulindac, which increases apoptosis at the lumen surface, is such an agent. The effect of intermittent pulse drug treatment schedules were compared with constant drug treatment schedules. Crypts treated with intermittent pulse schedules have three times the maximum tolerated dose than crypts treated with constant schedules, and have a 10 year delay in the appearance of adenomas. Intermittent treatment schedules have previously been proposed for chemoprevention. Here computer simulations have quantified the effect on human colon crypts of intermittent treatment schedules and constant treatment schedules of a chemotherapeutic drug. Intermittent pulses have an advantage, they allow an increased maximum tolerated dose, and result in an increased chemoprevention by delay.