Functional Screening to Guide Personalized Cancer Therapy

Ex vivo functional drug screening of primary cells derived from patients with hematologic malignancies represents a complementary approach to emerging genomic technologies. Deep sequencing technologies have revolutionized our capacity to decode cancer genomes and identify driver mutations. However, in many instances knowledge of somatic drivers has not yet resulted in new therapeutic strategies and the implementation of new therapeutic strategies has lagged far behind the ability to initially recognize operationally important genetic lesions. Until we have further bridged this gap between identification of genetic lesions and resultant knowledge of effective therapies, alternative strategies for rapidly identifying candidate therapies for patients can be an important tool. My lab has developed ex vivo, functional screening platforms that can be applied directly to primary specimens from patients with hematologic malignancies to identify candidate therapies on an individualized basis. These assays are based on panels of drugs and deliver information about the specific drugs (or combinations of drugs) to which a patient’s tumor cells are sensitive. Integration of these functional data with genomic information about each patient’s tumor cells has allowed us to accelerate the process by which we discover actionable therapeutic strategies that correlate with tumor genotypes and epigenetic events. Additionally, these assays incorporate certain elements of the tumor microenvironment and so can deliver information regarding drug sensitivity that may be driven by tumor-stromal interactions, which may not be apparent from genomic analyses alone. We have also tested a series of drug combinations that have revealed unexpected and promising drug synergies, especially when coupling agents across drug classes (e.g. inhibitors of signaling pathways with transcriptional regulators). Finally, these assays are completed in a clinically relevant time frame of three days, such that the data from these assays can be used to directly inform therapeutic strategies, even in the absence of genomic information. We have initiated clinical trials that make use of the ex vivo drug data to select individualized therapies for patients with a variety of hematologic malignancies and also serve as a pre-screening tool for enrollment of patients most likely to respond to particular agents. In this lecture, I will provide an overview of these functional screening platforms, which will include discussion of data integration strategies enabling correlation of targeted therapies with genetic and epigenetic events. I will discuss our initial experience with predicting and testing drug combinations. Finally, I will discuss strategies for implementation of functional screening assays into clinical trials both as a stand-alone tool as well as concepts for integrating functional and genomic data into a clinical trial format.