Bio
Cancer Biology, Precision Diagnostics, and Drug Development
Research Topics: All cancers must accumulate molecular changes to achieve sustained growth, evade apoptosis, achieve immortality, acquire a blood supply, invade tissue barriers, and finally establish metastasis. Three of these six functional capacities can arise through the mutation of several genes involved in cell cycle regulation and apoptosis, Wnt signaling, RPTK signaling, and TGF-β signaling pathways. Our long-term research objective is to identify, quantify, and correlate the multi-gene DNA and RNA alterations that activate the functional capacities of a given tumor. Understanding the molecular profiles of both primary adenocarcinomas and metastasis provides the basis for improving early detection, refining current treatment protocols, and developing new gene-specific therapies. We have developed a new class of drugs termed “coferons”, which can enter cells as small monomers, and then self-assemble on the target to interfere with activity or protein-protein interactions. We have combined the best of Coferon Linker Technology and first-generation Protein Degrader technology known as PROTACs to create CURE PROs (Combinatorial Ubiquitination REal-time PROteolysis). CURE-PRO monomers are smallmolecules that work as pairs; one is composed of a ligand that binds to a target protein and a linker element, while the other comprises a ligand that binds to an E3 ligase and a complementary linker element. Once inside the cells, they bind to their respective targets, self-assemble using their reversible linker chemistries to form a CURE-PRO dimer that brings the target protein and E3 ligase together, triggering degradation of the target protein by the cell’s natural recycling machinery, known as the ubiquitin proteasome system UPS). These approaches are currently being applied to novel cancer targets where traditional inhibitors have failed.
Our laboratory, funded by an NCI program project grant that was implemented to achieve a comprehensive molecular profiling of colon tumors has led to the formation of projects involved in cancer screening and cancer treatment. Our approach used two complementary molecular profiling techniques on the same human tumor sample: (i) determining the genetic and epigenetic profiles (see unique technologies below), and (ii) determining mRNA profiles, and then correlating the results. We have extended these results to include epigenetic profiling of tumors, which has become the cornerstone of our newly developed liquid biopsy assays. We have used multiplexed PCR profiling of plasma samples to develop a machine learning algorithm to detect colorectal cancer at the earliest stages 1 and 2, exceeding sensitivities and specificities of more costly NGS approaches. Our long-term goal is to democratize cancer care, providing a suite of highly scalable diagnostic and prognostic assays that are affordable across the globe. This includes providing a continuum of Cancer Care, starting with identifying patients at higher risk for cancer, screening patients for early cancer, diagnosing patients with early cancer, guiding patient treatment decisions, monitoring patient treatment efficacy, monitoring patient for early recurrence, and guiding patient for recurrence treatment.
Lab Organization and Equipment: The Barany laboratory is relatively small but collaborates extensively with both academic and industrial researchers. The laboratory has developed sensitive and specific assays using Nanopore Sequencing, DNA microarrays, Real time and Digital PCR, and thermostable ligase for these applications. The laboratory has state-of-the-art equipment including the latest generation of Nanopore Sequencers, Real-time Thermocyclers, Digital PCR Thermocyclers, PCR thermocyclers, Acoustic Droplet Liquid Handler, WES Protein Simple, and several automated robotic workstations to help with high-throughput analyses.
Past Contributions and Future Developments: The Barany laboratory is best known for developing the ligase chain reaction (LCR), ligase detection reaction (LDR), a programmable DNA chip (Universal Array), Coferons, and most recently CURE-PROs. Other advances include the EndoV/Ligase mutation scanning assay and harmonized p53 mutation detection. We are currently collaborating with industrial partners to develop new Nanopore sequencing and Taqman-based assays to detect promoter methylation, quantify gene copy number changes, protein and RNA changes associated with cancer.