Robust Control of Evolutionary Dynamics: Case studies in HIV/Antibody Therapy and Non-small Cell Lung Cancer (NSCLC)

Friday, November 20, 2015 - 11:15am - 11:30am
Keller 3-180
Vanessa Jonsson (California Institute of Technology)
The application of principles from evolutionary biology has long been used to gain new insights into the progression and clinical control of both infectious diseases and neoplasms. This iterative evolutionary process consists of expansion, diversification and selection within an adaptive landscape - species are subject to random genetic or epigenetic alterations that result in variations; genetic information is inherited through asexual reproduction and strong selective pressures such as therapeutic intervention can lead to the adaptation and expansion of resistant variants. These principles lie at the center of modern evolutionary synthesis and constitute the primary reasons for the development of resistance and therapeutic failure, but also provide a framework that allows for more effective control.

We propose an integrated experimental and computational framework for the rational design of treatment strategies to control evolution of resistance that also allows for the ability to quantifiably explore tradeoffs in treatment design, such as limiting the number of candidate therapies in the combination, dosage constraints and robustness to model error. This methodology is primarily based on the application of recent results in optimal control of positive systems to an evolutionary dynamics model and is constructed from experimentally derived growth, mutation, and pharmacodynamics data. We apply these algorithms to synthesize treatment strategies for two model evolutionary systems 1) the treatment of chronic HIV-1 infection by broadly neutralizing antibody (bNAb) therapy, and 2) the treatment of non-small cell lung cancer (NSCLC) with small molecule inhibitors. We show preliminary in vitro studies that suggest that the treatment strategies predicted by our algorithms can effectively address heterogeneous populations and control evolution to resistance.

NSCLC work is done in collaboration with Trever Bivona, Collin Blakely (UCSF). HIV work is done in collaboration with Anders Rantzer (Lund) and Nikolai Matni (Caltech), with experiments performed in the laboratory of David Baltimore (Caltech).