Biology subjects

Robertson-Tessi, M.

Publications and source records attributed to Robertson-Tessi, M..

3 recordsLinked to original sources

bioRxiv2018

Evolutionary exploitation of PD-L1 expression in hormone receptor positive breast cancer

Based on clinical data from hormone positive breast cancer patients, we determined that there is a potential tradeoff between reducing tumor burden and altering metastatic potential when administering combination therapy of aromatase inhibitors and immune checkpoint inhibitors. While hormone-deprivation therapies serve to reduce tumor size in the neoadjuvant setting pre-surgery, they may induce tumors to change expression patterns towards a metastatic phenotype. We used mathematical modeling to explore how the timing of the therapies affects tumor burden and metastatic potential with an eye toward developing a dynamic prognostic score and reducing both tumor size and risk of metastasis.

cancer biology↗

bioRxiv2018

Hybrid Automata Library

The Hybrid Automata Library (HAL) is a Java Library developed for use in mathematical oncology modeling. It is made of simple, efficient, generic components that can be used to model complex spatial systems. HALs components can broadly be classified into: on- and off-lattice agent containers, finite difference diffusion fields, a GUI building system, and additional tools and utilities for computation and data collection. These components are designed to operate independently and are standardized to make them easy to interface with one another. As a demonstration of how modeling can be simplified using our approach, we have included a complete example of a hybrid model (a spatial model with interacting agent-based and PDE components). HAL is a useful asset for researchers who wish to build efficient 1D, 2D and 3D hybrid models in Java, while not starting entirely from scratch. It is available on github at https://github.com/torococo/HAL under the MIT License. HAL requires at least Java 8 or later to run, and the Java JDK version 1.8 or later to compile the source code.\n\n1 Author SummaryIn this paper we introduce the Hybrid Automata Library (HAL) with the purpose of simplifying the implementation and sharing of hybrid models for use in mathematical oncology. Hybrid modeling is used in oncology to create spatial models of tissue, typically by modeling cells using agent-based techniques, and by modeling diffusible chemicals using partial differential equations (PDEs). HALs key components are designed to run agent-based models, PDEs, and visualization. The components are standardized and are completely decoupled, so models can be built with any combination of them. We first explore the philosophy behind HAL, then summarize the components. Lastly we demonstrate how the components work together with an example of a hybrid model, and a walk-through of the code used to construct it. HAL is open-source and will produce identical results on any machine that supports Java 8 and above, making it highly portable. We recommend HAL to modelers interested in spatial dynamics, even those outside of mathematical oncology, as the components are general enough to facilitate a variety of model types. A community page that provides a download link and online documentation can be found at https://halloworld.org [1].

cancer biology↗

bioRxiv2018

The immune checkpoint kick start: Optimization of neoadjuvant combination therapy using game theory

An upcoming clinical trial at the Moffitt Cancer Center for women with stage 2/3 ER+breast cancer combines an aromatase inhibitor and a PD-L1 checkpoint inhibitor, and aims to lower a preoperative endocrine prognostic index (PEPI) that correlates with relapse-free survival. PEPI is fundamentally a static index, measured at the end of neoadjuvant therapy before surgery. We develop a mathematical model of the essential components of the PEPI score in order to identify successful combination therapy regimens that minimize both tumor burden and metastatic potential, based on time-dependent trade-offs in the system. We consider two molecular traits, CCR7 and PD-L1 which correlate with treatment response and increased metastatic risk. We use a matrix game model with the four phenotypic strategies to examine the frequency-dependent interactions of cancer cells. This game was embedded into an ecological model of tumor population growth dynamics. The resulting model predicts both evolutionary and ecological dynamics that track with changes in the PEPI score. We consider various treatment regimens based on combinations of the two therapies with drug holidays. By considering the trade off between tumor burden and metastatic potential, the optimal therapy plan was found to be a 1 month kick start of the immune checkpoint inhibitor followed by five months of continuous combination therapy. Relative to a protocol with both therapeutics given together from the start, this delayed regimen results in transient sub-optimal tumor regression while maintaining a phenotypic constitution that is more amenable to fast tumor regression for the final five months of therapy. The mathematical model provides a useful abstraction of clinical intuition, enabling hypothesis generation and testing of clinical assumptions.

cancer biology↗