Assessment of Clinical Response to V937 Oncolytic Virus After Intravenous or Intratumoral Administration Using Physiologically-Based Modeling.

Oncolytic viruses (OVs) represent a potential therapeutic strategy in cancer treatment. However, there is currently a lack of comprehensive quantitative models characterizing clinical OV kinetics and distribution to the tumor. In this work, we present a mechanistic modeling framework for V937 OV, after intratumoral (i.t.) or intravascular (i.v.) administration in patients with cancer. A minimal physiologically-based pharmacokinetic model was built to characterize biodistribution of OVs in humans. Viral dynamics was incorporated at the i.t. cellular level and linked to tumor response, enabling the characterization of a direct OV killing triggered by the death of infected tumor cells and an indirect killing induced by the immune response. The model provided an adequate description of changes in V937 mRNA levels and tumor size obtained from phase I/II clinical trials after V937 administration. The model showed prominent role of viral clearance from systemic circulation and infectivity in addition to known tumor aggressiveness on clinical response. After i.v. administration, i.t. exposure of V937 was predicted to be several orders of magnitude lower compared with i.t. administration. These differences could be overcome if there is high virus infectivity and/or replication. Unfortunately, the latter process could not be identified at the current clinical setting. This work provides insights on selecting optimal OV considering replication rate and infectivity.

Strategies and Recommendations for Using a Data-Driven and Risk-Based Approach in the Selection of First-in-Human Starting Dose: An International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Assessment.

Various approaches to first-in-human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access. In addition, ambiguity exists in how MABEL is defined and the methods used to determine it. The International Consortium for Innovation and Quality in Pharmaceutical Development convened a working group to understand current use of MABEL and its impact on FIH starting dose selection, and to make recommendations for FIH dose selection going forward. An industry-wide survey suggested the achieved or estimated maximum tolerated dose, efficacious dose, or recommended phase II dose was > 100-fold higher than the MABEL-based starting dose for approximately one third of NMEs, including trials in patients. A decision tree and key risk factor table were developed to provide a consistent, data driven-based, and risk-based approach for selecting FIH starting doses.

Spatial modeling of dimerization reaction dynamics in the plasma membrane: Monte Carlo vs. continuum differential equations.

Bimolecular reactions in the plasma membrane, such as receptor dimerization, are a key signaling step for many signaling systems. For receptors to dimerize, they must first diffuse until a collision happens, upon which a dimerization reaction may occur. Therefore, study of the dynamics of cell signaling on the membrane may require the use of a spatial modeling framework. Despite the availability of spatial simulation methods, e.g., stochastic spatial Monte Carlo (MC) simulation and partial differential equation (PDE) based approaches, many biological models invoke well-mixed assumptions without completely evaluating the importance of spatial organization. Whether one is to utilize a spatial or non-spatial simulation framework is therefore an important decision. In order to evaluate the importance of spatial effects a priori, i.e., without performing simulations, we have assessed the applicability of a dimensionless number, known as second Damköhler number (Da), defined here as the ratio of time scales of collision and reaction, for 2-dimensional bimolecular reactions. Our study shows that dimerization reactions in the plasma membrane with Da approximately >0.1 (tested in the receptor density range of 10(2)-10(5)/microm(2)) require spatial modeling. We also evaluated the effective reaction rate constants of MC and simple deterministic PDEs. Our simulations show that the effective reaction rate constant decreases with time due to time dependent changes in the spatial distribution of receptors. As a result, the effective reaction rate constant of simple PDEs can differ from that of MC by up to two orders of magnitude. Furthermore, we show that the fluctuations in the number of copies of signaling proteins (noise) may also depend on the diffusion properties of the system. Finally, we used the spatial MC model to explore the effect of plasma membrane heterogeneities, such as receptor localization and reduced diffusivity, on the dimerization rate. Interestingly, our simulations show that localization of epidermal growth factor receptor (EGFR) can cause the diffusion limited dimerization rate to be up to two orders of magnitude higher at higher average receptor densities reported for cancer cells, as compared to a normal cell.

Computational modeling reveals molecular details of epidermal growth factor binding.

BACKGROUND: The ErbB family of receptors are dysregulated in a number of cancers, and the signaling pathway of this receptor family is a critical target for several anti-cancer drugs. Therefore a detailed understanding of the mechanisms of receptor activation is critical. However, despite a plethora of biochemical studies and recent single particle tracking experiments, the early molecular mechanisms involving epidermal growth factor (EGF) binding and EGF receptor (EGFR) dimerization are not as well understood. Herein, we describe a spatially distributed Monte Carlo based simulation framework to enable the simulation of in vivo receptor diffusion and dimerization. RESULTS: Our simulation results are in agreement with the data from single particle tracking and biochemical experiments on EGFR. Furthermore, the simulations reveal that the sequence of receptor-receptor and ligand-receptor reaction events depends on the ligand concentration, receptor density and receptor mobility. CONCLUSION: Our computer simulations reveal the mechanism of EGF binding on EGFR. Overall, we show that spatial simulation of receptor dynamics can be used to gain a mechanistic understanding of receptor activation which may in turn enable improved cancer treatments in the future.

Time accelerated Monte Carlo simulations of biological networks using the binomial tau-leap method.

UNLABELLED: Developing a quantitative understanding of intracellular networks requires simulations and computational analyses. However, traditional differential equation modeling tools are often inadequate due to the stochasticity of intracellular reaction networks that can potentially influence the phenotypic characteristics. Unfortunately, stochastic simulations are computationally too intense for most biological systems. Herein, we have utilized the recently developed binomial tau-leap method to carry out stochastic simulations of the epidermal growth factor receptor induced mitogen activated protein kinase cascade. Results indicate that the binomial tau-leap method is computationally 100-1000 times more efficient than the exact stochastic simulation algorithm of Gillespie. Furthermore, the binomial tau-leap method avoids negative populations and accurately captures the species populations along with their fluctuations despite the large difference in their size. AVAILABILITY: http://www.dion.che.udel.edu/multiscale/Introduction.html. Fortran 90 code available for academic use by email. SUPPLEMENTARY INFORMATION: Details about the binomial tau-leap algorithm, software and a manual are available at the above website.