Translational Insights for the Precision Treatment of Peripheral T-cell Lymphomas

This work addresses a persistent challenge presented by the heterogeneous drug sensitivities of peripheral T-cell lymphomas (PTCL), where there are many options for treatment, but therapies are only effective for small subsets of PTCL patients, and the molecular drivers of drug sensitivity shared among these small patient subsets are not currently well-defined. The influence of molecular heterogeneity on drug sensitivity is multi-faceted, and therefore this thesis employs functional genomics, preclinical drug screening, proteomic profiling, and computational modeling to identify and demonstrate the impact of biomarkers selection in PTCL treatment. Chapter 1 outlines the development of PTCL classification and treatment, framing the need for subtype-specific treatment strategies to improve upon the current underperforming landscape of PTCL treatments. Chapter 2 makes use of preclinical drug sensitivity measurements with two histone deacetylase (HDAC) inhibitors, romidepsin and belinostat, that are used to treat PTCL to determine if the clinically-observed, subtype-specific efficacy of romidepsin can be applied to the design for an upcoming trial of belinostat. Chapter 3 addresses a challenge in the identification of biomarkers of drug sensitivity. Where previous attempts at correlating drug sensitivity with mutations or expression profiles for various cancers have elected many possible candidate biomarkers, it is often difficult to pinpoint true drivers of drug sensitivity due to the covariance of many of these features and their altered significance upon adjustments for multiple hypothesis testing. We integrate functional genomic screens with proteomic profiling across multiple human cell culture models to uncover biomarkers that are predictive of drug sensitivity in PTCL. Mechanistically distinct, predictive features are identified for therapies including the antifolate therapy, pralatrexate, for which the reduced folate carrier, SLC19A1, is shown to both positively correlate with and confer drug sensitivity upon knockdown to pralatrexate. Together, these chapters provide experimental foundation and rationale for refining PTCL treatment through molecular stratification, and this work more generally supports the precise administration of small molecule therapies in oncology.