Quantitative Cancer Modeling Research Group

Staff Research Interests
Philip Hahnfeldt, PhD
Principal Investigator
• Cancer growth dynamics
• Radiotherapeutic and chemotherapeutic dosing
• DNA damage and repair
• Tumor angiogenesis modeling
• Gene interaction networks
Lynn Hlatky, PhD
CCSB Director
• Cell-cell interactions
• Self-organization and emergence
• Stability criteria for interaction subpopluations
• Evolutionary dynamics
Christine E. Briggs, PhD
Assistant Investigator
• Defining microRNA profiles and targets involved in cancer and response to irradiation
• Defining methylation profiles associated with dysregulation of genes/molecular pathways involved in cancer and response to irradiation
• Applying aCGH, methylation/SNP-microarray and NGS technologies to identify regions of genomic instability associated with cancer and response to irradiation
Sébastien Benzekry, PhD
• Modeling of metastatic development and tumor-tumor interacations
• Modeling of the angiogenesis process
• Structured equations in population dynamics
• Scheduling optimization for anti-cancerous therapies
Xuefeng (Ryan) Gao, PhD
Postdoctoral Fellow
• Modeling tumor growth, tumor angiogenesis, and invasion
• Darwin evolution of cancer cells: the emergence and distribution of cancer cell phenotypes
• Modeling cancer gene therapies (e.g., virotherapy, bacterial therapy)
• Dynamics of multi-cellular systems
• Cell-centered multi-scale modeling and simulation
• Biomedical visualizations, animations and movies
• Interactive technologies
Rainer Sachs, PhD
Associate Investigator
• Radiation-induced carcinogenesis
• Chronic myeloid leukemia (CML)
• Cosmic radiation risk estimation for astronauts
• Second cancers after radiotherapy
• Radiation-induced chromosome aberrations
• Large-scale geometry of chromatin during cell cycle interphase
Kathleen Wilkie, PhD
Assistant Investigator
• Cell adhesion and the extracellular matrix
• Tissue-matrix remodelling
• The effects of mechanical stresses on cells
• Heterogeneous cell populations in cancer progression
• Growth, development, and aging effects on biological tissues
• Mechanical properties of biological tissues


Mathematical Research at the CCSB

quantitative_modeling Quantitative research at the CCSB embraces the principle that cancer is not just a disease of cells, but is facilitated at the population and inter-tissue levels. Accordingly, a multi-level approach must be implemented to fully understand its origin and course. Initial events in carcinogenesis occur within cells at the molecular level as repair and proliferation dysfunctions, leading to genomic instability, aneuploidy, and final transformation. But after cancer cell creation, the clone advances to encounter additional molding and fate-determining events defined by cell-cell interactions. The associated stroma (fibroblasts and extracellular matrix) plays a critical role in cancer progression, as does induced tumor vascularization (angiogenesis). Both act to determine whether a nascent cancer advances to become symptomatic disease. Without stromal activation and angiogenesis, tumor development is halted early. Under NASA Specialized Centers of Research (NSCOR) funding, these studies are focusing on the determination of cancer risk to astronauts who will be exposed to harmful solar particle events (SPEs) and galactic cosmic radiations (GCRs) during long-term space flight. By extension, we hope to better understand the carcinogenesis process more generally, and discover new therapeutic interventions for improved cancer treatment.

The origin of cancer may be attributed to events that alter the repair machinery of the cell and destabilize its genome. Of active interest in this regard is how nucleotide-level DNA damage and repair translates into chromosome aberrations, as chromosome-level misrepair is the feature most closely identified with carcinogenic transformation. By developing a revised theory for double-strand break repair/misrepair following ionizing radiation, we have found it possible to improve upon the commonly-accepted repair models, thus providing a better template for surrogate radiation cancer risk estimation.

We have gone on to associate radiation action to the first population-level bottleneck limiting the growth of hyperplastic clones through a process of self-limited cell growth. The resulting deterministic model for early carcinogenesis has proven to be competitive with the current stochastic standard in explaining major epidemiological data sets on radiation-induced carcinogenesis.

A second bottleneck encountered early in carcinogenesis is nutrient availability. Without angiogenesis, a tumor cannot grow beyond approximately 1mm in size. This obstacle to tumor growth requires the development of angiogenic potential within the growing clone of tumor cells — an ‘angiogenic switch’. Interestingly, it was discovered quite by accident some time ago while performing autopsies on adults who died of non-cancer causes (Black and Welch, 1993 and Black and Welch, 2010) that most middle-aged people harbor dormant, non-threatening cancer lesions. Held back by the failure to initiate angiogenesis, the tumors remained harmless throughout these individuals' lifetimes. One major objective of our Center is to understand how such a stasis may be maintained, and perhaps re-established, as part of a novel therapeutic approach. We have made inroads into quantitatively understanding this natural control in tumor growth and how antiangiogenic therapy might best be applied to achieve this goal.

self-metastases Basic Cell Kinetics, Cancer Stem Cells, and Tumor Morphology
Tumors are intrinsically heterogeneous. The majority of the tumor cells have limited life span and replicative potential, and only a small minority (so-called cancer stem cells) live forever, divide infinitely and potentially produce more such stem cells. It is these stem cells that determine tumor formation, and their dynamics is counterintutively inhibited by their non-stem progeny. Only a high migration rate can liberate stem cells and enable their migration to seed new clones in the vicinity of the original cluster. In this manner, the tumour continually ‘self-metastasizes’.

We use cellular automaton models to define the behavior of single cells, and then let single cells populate a compuational domain. As the number of cancer cell increases over time competition for environmental resources (such as space) defines population dynamics. A result is a cancer cell population (a tumor) growing sub-exponentially. Tumor progession is dictated by the ability of stem cells to form self-metastases that together form a malignant invasive morphology.

Modeling DNA Damage and Repair and Chromosome Geometry dna damage
The chromosome damage/repair studies have interrelated results on cytogenetics and interphase chromosome localization and geometry. By developing a revised theory for double-strand break repair/misrepair following ionizing radiation, we found it possible to improve upon the commonly-accepted repair models, in the process obtaining information on how chromosomes are packaged within the nucleus. Incomplete exchange models developed from these studies were also able to explain the relation between acentric and dicentric counts and the excess dispersion (variance/mean) for the number of acentric fragments relative to dicentrics seen in human lymphocytes exposed to various radiation types and doses.

self metastasesAngiogenesis Modeling and Anti-angigenic Therapy
Extending from collaboration with the late Dr. Judah Folkman of Children's Hospital Boston, we are exploring the unique tumor/vascular regression kinetics of anti-angiogenic therapy. The indirect means by which tumor suppression is here accomplished, coupled with the recent finding that tumors both stimulate and inhibit their own vascularization, points to a need to formulate tumor-vascular models that properly capture the dynamics. We use sets of differential equations that simultaneously consider vascular response to anti-angiogenic agents and subsequent suppression of tumor growth. The result is a formalism that is proving to be both explanatory and clinically predictive. This work is an example of quantitative translational research, a “workstation-to-bench-to-bedside” research strategy embraced by the CCSB. An important dynamic to surface from these studies is the self-imposed Gompertz restriction on growth imposed by a tumor on itself. Implications for the general organogenic control of tissue mass are suggested. Another study of dose rate effects addresses an as yet un-quantified effect — the utility of so-called “metronomic” (small, evenly-spaced) dosing on the treatment response of a tumor population. It was shown considering the response of a heterogeneous target to various dosing protocols that: 1) metronomic dosing does indeed offer the best tumor suppression, and 2) the shift to metronomic dosing from more traditional “up-front” dosing regimens favors the endothelial cell compartment. The theory offers one explanation for numerous reports of an antiangiogenic response using the metronomic scheme.

Tumor Heterogeneity
tumor heterogeneity A unifying theme in both the DNA repair and angiogenesis studies is the role tumor heterogeneity and inter-tissue interactions play in carcinogenesis risk and cancer treatment response. Under our NASA NSCOR Program Project dedicated to examining how inter-cellular interactions modulate carcinogenesis, we are currently employing quantitative methods to understand the unifying mechanisms more precisely. A deterministic carcinogenesis risk model that incorporates cell-cell interactions was developed which compares favorably to the current stochastic model standard in explaining epidemiologic data on atom bomb survivors. Additional unpublished studies are now showing that inter-cellular interactions may even decide the course of cancer after the fact of tumor cell creation, proving these interactions to be a vital augment to current cell-centric focuses on cancer origin and treatment response.


Our BioInformatics and Network Statistics Group uses high-throughput data from both in-house and external data sources to investigate molecular targets, molecular pathways, and molecular networks to inform our clinical and biological staff concering potential new targets and new biology. In addition, we are investigating the interaction of -omics data with cellular macroscopic images to go beyond the conventional views of molecular and cellular biology.


Chromosome Aberration Simulator (CAS)
Software for simulating radiogenic aberrations in detail. Executables and source code are freely available for any educational or research purpose.
Chromosome Aberration Analyzer (CAA)
Software for quantitative analyses of observed or simulated karyotypes.

Representative Publications:
The following articles on the topic of quantitative modeling have been published by researchers at CCSB: