Dr. Samantha Pattenden, Associate Professor, joined the CICBDD in 2010 as a Postdoctoral Research Associate and in 2015 was promoted to Assistant Professor, Director of Applied Epigenetic Screening Technologies. In 2017 she co-founded Triangle Biotechnology, Inc. with Dr. Paul Dayton (Biomedical Engineering). Read how this company was helped in UNC’s Kickstart Accelerator.
Next to Sam in the photo is Merrill Froney, Graduate Research Associate, who currently works on a grant with Dr. Mike Jarstfer, developing a high throughput screen for identifying cancer drug candidates. She aspires to work in the pharmaceutical industry once she graduates. Under Sam in the photo is Oscar Jaimes, Research Technician. He has always wanted to be a dentist. He will finish his time with us this summer to begin dental school. Next to Oscar is Christian Cook, an undergraduate student in Chemistry. He is working with Merrill to assess cell viability in the presence of small molecule chemical inhibitors. On the bottom row we have Nick Chamberlain, Research Technician, who aspires to work in academia. He will start his graduate studies at Northwestern University this fall in the Interdisciplinary Biological Sciences program. Next Marjan Mohseni, Research Associate, who splits her time with Dr. Paul Dayton (Biomedical Engineering) is the lab expert in sonication technology. She recently participated in the development of a novel high throughput sonication platform.
The Pattenden Lab develops innovative techniques in chromatin-based therapeutic target discovery and cancer diagnostics. Our research program enables discovery of novel molecular targets, pathways and mechanisms. Some of our current projects include:
Innovative new technologies that enable experimentally robust interrogation of epigenetic mechanisms are needed to broaden our understanding of epigenetic regulatory pathways in human development, disease, and therapeutic resistance. Formalin fixed, paraffin embedded (FFPE) tissues contain a wealth of information on human disease, however, extraction of high-quality chromatin (DNA together with associated nuclear proteins) from these samples for use in epigenetic assays has proven virtually impossible. We are exploring the use of a unique cavitation enhancement reagent in simplifying and standardizing chromatin extraction from FFPE tissues, with the goal of making archived biospecimens available for a broad range of epigenetic-based biomedical research.
As appreciation of the importance of chromatin dysregulation in cancers has grown, chromatin regulatory proteins have emerged as promising targets for therapeutic discovery. Unlike alterations to the underlying DNA sequence, changes in chromatin states are both dynamic and reversible. Chromatin-related proteins are challenging targets for small molecule discovery since they frequently associate with multiple complexes with divergent cellular functions. For this reason, hit compounds derived from in vitro screening approaches based on a single chromatin-associated protein domain will likely suffer from significant off-target effects when tested in cells or in vivo.
To address the immediate need for cell-based chromatin screens, we have developed a target agnostic small molecule screening technology that exploits tumor-specific chromatin accessibility states as a relevant and direct functional readout. By targeting chromatin accessibility instead of a single transcription factor or chromatin regulatory protein, the limitations associated with in vitro screening and single protein target identification can be overcome. This screening technique represents a promising new paradigm in oncology drug discovery that will increase our mechanistic knowledge of tumor-specific changes in the epigenome and expand the repertoire of druggable targets.
Cancerous cells develop a number of mechanisms to evade the checks and balances present in normal cells. One of the mechanisms by which tumor cells become immortal is by maintaining the length of the caps at the ends of chromosomes called telomeres. Telomere length is maintained by telomerase in ~85% of cancers and by the alternative lengthening of telomeres (ALT) pathway in the remaining ~15% of cancers. The ALT pathway is associated with poor prognosis, but the mechanisms by which ALT is induced are not well understood. ALT cells are frequently associated with the formation of extrachromosomal C-circles, which can be used as a readout for ALT activity. We are developing a high throughput assay using targeted small molecule chemical libraries to discover inhibitors of the ALT C-circle phenotype. Hit compounds will inform the key protein players in ALT maintenance and possibly reveal new therapeutic targets for ALT positive cancers.