Abstract PO5-24-09: Optimizing the Therapeutic Treatment of Breast Cancer Through a Dual Data-driven Theoretical Model

Abstract

Abstract Despite rapid advancements in treatments and technology, breast cancer remains the second leading cause of cancer related morbidity in women in the US. As a heterogeneous disease, the unique genetic and phenotypic profile of each tumor complicates the prediction of treatment responses and optimized treatment strategies. One primary manifestation of phenotypic plasticity and concomitant intra-tumoral heterogeneity is the Epithelial-Mesenchymal Transition (EMT). The acquisition of migratory and invasive properties through EMT facilitates tumor metastasis and results in worse patient outcomes. As a result, the EMT and its reverse process (MET) often influence treatment response. However, the different mechanisms through which these therapeutic drugs affect the EMT-related phenotypic switching rates as well as each phenotype’s replication rates are unclear, and further investigation is required for better understanding their precise effect for directing optimal treatment strategies and improved patient outcomes. Here, we compile an atlas of publicly available metastatic and non-metastatic RNA sequencing data of breast cancer cell lines treated with therapeutic and chemotherapeutic drugs and propose a dual data-driven theoretical framework for understanding the effects of each drug on breast cancer treatment response. We infer the cell fractions, EMT phenotypic transition rates and phenotypic replication rates of each case through an extension of our previously developed hybrid data-driven and theoretical model, COMET. We infer single-cell RNA sequencing-derived EMT-related trajectories and apply a continuous time Markov chain model to infer inter-state transition rates. By analyzing the atlas of RNA sequencing data and integration with our framework, we gain novel insights into the context-specific mechanisms by which therapeutic drugs affect the phenotypic transition rates. This comprehensive understanding will contribute to optimizing breast cancer therapy and ultimately improving patient outcomes. Citation Format: A. Najafi. Optimizing the Therapeutic Treatment of Breast Cancer Through a Dual Data-driven Theoretical Model [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-24-09.