Modeling in Medicine: Case Studies in Cancer and COVID-19February 17, 2023 at 1:30–2:20 p.m.

Modeling and simulation is widely used in engineering for technology development, but rarely
used for therapy development. In this seminar, I will present two case studies of how we are
using physics-based modeling to advance fundamental, translational, and clinical science. The
first case study focuses on cancer, in particular glioblastoma, which remains a deadly cancer
driven by invasion of tumor cells into the brain. Transcriptomic analyses have revealed distinct
molecular subtypes, but mechanistic and targetable differences are not clear. Using a state-of-
the-art immunocompetent mouse model for glioblastoma, we found that, as predicted by the
motor-clutch model for cell migration (Chan and Odde, Science, 2008; Klank et al., Cell Rep,
2017), mesenchymal glioma cells are more spread, generate larger traction forces, and
migrate faster in brain tissue compared to proneural cells. These findings open up new
opportunities for subtype-specific therapies. In addition, our model enabled discovery of
negative durotaxis, i.e. preferential migration toward softer environments, which will allow us to
predict cancer progression with greater accuracy. The second case study focuses on
mathematical modeling of SARS-CoV-2 replication. We found that that some steps, including
protein translation, are especially good targets, while others, such as those mediating viral
entry, were relatively poor targets. Remarkably, in the subsequent two years since we
developed the model, we found that it has accurately predicted 7 out 7 drugs as recommended
for or against in the NIH COVID-19 Treatment Guidelines. In addition, the model motivated a
phase 3, double-blind, randomized, placebo-controlled clinical trial in the early outpatient
setting for metformin (COVID-OUT; NCT04510194). We found a 42% reduction in
hospitalization/ED visits in the first 14 days (aOR=0.58; 95% CI, 0.35 to 0.94). In addition, we
found a 42% reduction in Long Covid (PASC) over a 10 month follow-up period (HR=0.58;
95% CI 0.38 to 0.88). Given that metformin is available globally, well-tolerated, and
inexpensive ($0.48 per course of treatment), it could provide an important new tool for limiting
the impacts of both acute and Long Covid world-wide.