Tyrosine Kinase Inhibitors (TKIs) are molecularly-targeted therapies that have dramatically improved progression-free survival in non-small cell lung cancer. However, even these remarkable drugs are ultimately rendered ineffective by innate or acquired resistance. âIn vitro âscreening with single cell sequencing provides insight into cell-cell heterogeneity and cancer-associated pathway activation, allowing identification of potentially viable combination therapies that can overcome resistance. However, single cell sequencing approaches require specialized and costly microfluidics that limit the number of drugs that can be tested. In this project, we will develop a transformative new drug screening technology that will overcome the barriers of current methods, thereby accelerating preclinical drug discovery. In contrast to current methods that use microfluidics to encapsulate and barcode single cell transcriptomes, our approach uses bulk self assembly facilitated by pre-templated instant partitions (PIPs); PIPs remove microfluidics from the process, dramatically reducing cost. Moreover, unlike microfluidic methods, our approach integrates seamlessly with laboratory automation and 384-well formats, allowing hundreds of drugs to be tested simultaneously. The Aims of the project will be to transfer the current academic protocol to our industrial setting, optimizing it for reaction efficiency and reliability, and to characterize the resultant Alpha kit against cancer cell lines treated with gefitinib, a well-characterized TKI for lung adenocarcinomas.
Public Health Relevance Statement: Project Narrative Most anti-cancer drugs are ultimately rendered ineffective by resistance. The objective of this proposal is to develop a new drug screening technology that will allow screening of large compound libraries to identify combination therapies that will overcome drug resistance. This technology relies on the core innovation of our company for performing single cell genomics using a bulk self assembly process that requires no microfluidics or specialized equipment.
Project Terms: Affect; Antineoplastic Agents; Antitumor Drug Screening Assays; Automation; Biological Assay; Biological Sciences; Cancer cell line; Cell Line; Cells; Chromium; combinatorial; Combined Modality Therapy; cost; cost effective; Data; Drug Combinations; drug discovery; Drug resistance; Drug Screening; drug sensitivity; Encapsulated; Equipment; Evaluation; Exposure to; Gefitinib; Gene Expression; Generations; Genomics; Heterogeneity; improved; In Vitro; individual response; Industrialization; innovation; insight; instrument; Laboratories; Legal patent; Libraries; Lung Adenocarcinoma; Malignant Neoplasms; Methods; Microfluidics; molecular targeted therapies; neoplastic cell; Non-Small-Cell Lung Carcinoma; novel strategies; novel therapeutics; Nucleic Acids; off-patent; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phenotype; Population; pre-clinical; Process; Progression-Free Survivals; Property; Protocols documentation; prototype; Reaction; Reproducibility; Resistance; resistance mechanism; Resolution; response; Sampling; screening; self assembly; single cell sequencing; single-cell RNA sequencing; Technology; Technology Transfer; Testing; transcriptome; transcriptome sequencing; transcriptomics; Tyrosine Kinase Inhibitor; W
