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Modelling the Effects of Phenotypic Plasticity on Evolutionary and Targeted Therapies for Neuroblastoma
Together with Dr Matishalin Patel, an expert in evolutionary biology and a colleague at the University of Hull, I applied for and secured a DAIM PhD studentship after a competitive process. In January 2024, Francesca Covell became our first PhD candidate. An international collaboration with Dr Sabine Taschner-Mandl from St. Anna Children's Cancer Research Institute was established.
Neuroblastoma cells are known to intercovert between three phenotypes (ADRN, I-type, and MES) with 64 possible interconversion patterns. The three phenotypes resist different therapies. This property has implications for evolutionary therapy, which exploits the evolutionary dynamics within a tumour comprising subpopulations with different mutations. An example is adaptive therapy, which uses treatment-sensitive cancer cells to suppress their resistant peers.
In the first stage of the project, Fran built and validated a dynamical model with three homogeneous subpopulations containing ADRN, I-type, and MES neuroblastoma cells respectively. ADRN cells are typically more sensitive to treatment (like ALK inhibitors), but Dr Taschner-Mandl has experimented with MES phenotype–specific inhibitors. I-type cells resemble cancer stem cells. By solving initial value problems numerically, Fran tested the two inhibitor types separately while inducing each interconversion pattern in computer simulations. Based on the results, she selected two patterns that work well with the two inhibitor types respectively. They were investigated further by sensitivity and stability analysis. She concluded the first stage by proposing cyclic treatment schedules that combine the two patterns and the two inhibitor types strategically.
