The Latin rule of three (omne trium perfectum) principle can turn out to be good, bad or somewhere in between, depending on the situation. For Texas A&M University chemist Dr. Jonathan T. Sczepanski, it doesn’t get much better than earning three prestigious research grants in a matter of months, all aimed at making potential progress toward treating ribonucleic acid-mediated diseases — specifically, cancer.
Sczepanski, a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research and member of the Texas A&M Department of Chemistry faculty since 2015, began his summer buoyed by notice of two new awards from the National Institutes of Health (NIH) totaling more than $500,000 over two years. Both are R21 grants, a mechanism described by the NIH as “intended to encourage exploratory/developmental research by providing support for the early and conceptual stages of project development.” Roughly a month later, he earned a $200,000 High Impact High Risk award from CPRIT for his proposal, “Development of a novel class of PRC2 inhibitors comprised of mirror image RNA.“ Sczepanski’s was one of 18 HIHR grants totaling nearly $3.6 million and one of three awarded to Texas A&M researchers in the category, which funds projects expected to contribute major new insights and ideas into the diagnosis, treatment and prevention of cancers.
Sczepanski’s research focuses on the development of biomedical tools and potential cancer therapeutics using L-DNA and L-RNA, which are mirror-image versions of the same genetic polymers (i.e., D-DNA and D-RNA) found in the cells of all living organisms. Beyond being resistant to typical cellular-level mechanisms designed to degrade or destroy them, these mirror-image molecules aren’t found in nature, rendering them unrecognizable by cells and free to carry out their function. For Sczepanski’s purposes, he and his team are working to engineer L-DNA and L-RNA molecules capable of targeting disease-associated RNAs for applications in bioimaging, molecular diagnostics and therapy.
The first of Sczepanski’s two NIH grants, awarded through the National Institute of Biomedical Imaging and Bioengineering, focuses on the development of diagnostic tools based on microRNA profiling. MicroRNAs are short pieces of RNA that help turn genes on and off inside cells. Because microRNAs play a critical role in controlling the expression of human genes, Sczepanski says they also play a central role in diseases, including cancer. Cancer cells often are associated with the simultaneous misregulation of several microRNAs relative to normal cells of the same tissue.
“These cancer-specific microRNA ‘signatures’ can reveal significant information about the underlying disease,” Sczepanski added. “Technologies aimed at profiling microRNA expression patterns, such as those we propose, hold great promise for early cancer detection and diagnosis.”
His second NIH grant, awarded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, is aimed at developing a new approach for profiling chemical modifications on RNA. Similar to DNA, RNA is chemically modified in our cells. However, the precise functions of the majority of RNA modifications discovered to date either are poorly understood or unknown, despite emerging links between RNA chemical modifications and the initiation and progression of various developmental processes and related diseases.
“We hope to overcome this knowledge gap by developing an innovative sequencing technology that will facilitate the interrogation of poorly characterized RNA modifications in unprecedented detail.” Sczepanski said.
Meanwhile, Sczepanski’s CPRIT award — his first since the 2015 First-Time Tenure-Track Award that helped recruit him to Texas A&M — centers on the Polycomb Repressive Complex 2 (PRC2), a transcriptional repressor that regulates several crucial developmental and physiological processes in the cell. Recently, scientists have identified a strong link between PRC2 and cancer, as evidenced by the fact that several cancer types exhibit dysregulation and dysfunction of PRC2 proteins. As a result, substantial efforts have been devoted to developing PRC2 inhibitors as cancer therapeutics, the vast majority of which are small molecules targeting the active site.
“Preliminary studies have shown that inhibition of PRC2 decreases tumor growth and invasiveness, which highlights the potential benefits of PRC2 inhibitors for cancer treatment,” Sczepanski said. “Moreover, PRC2 inhibitors have shown promise in the treatment of multiple-drug resistant cancers and cancers that have no effective treatment currently, including bladder cancer and ovarian clear cell carcinoma. We propose to develop a pipeline for the discovery, characterization and optimization of a novel class of PRC2 inhibitors. Our approach, which relies on targeting the RNA-binding site of PRC2 rather than its active site, represents a significant departure from the status quo and is expected to overcome many of the limitations associated with current inhibitory strategies. Thus, if successful, this work will signify a major advance for treating cancers that are dependent on PRC2.”
In addition to microRNA targets and mirror-image molecules, Sczepanski also studies the process of DNA repair and epigenetics, which are intimately linked to cancer development and progression. Together with his Texas A&M research group, he continues to work on synthesizing “designer” chromatin that will enable them to uncover relationships between chromatin structure, DNA repair and epigenetics in the context of human biology and diseases.
Sczepanski earned his Ph.D. in chemistry at Johns Hopkins University in 2010 and completed an NIH/National Research Service Award (NRSA) Postdoctoral Fellowship at The Scripps Research Institute prior to coming to Texas A&M in 2015. He previously received a five-year, $1.25 million Maximizing Investigators’ Research Award (MIRA) in 2017 to support his pursuit of novel nucleic acid technologies for probing RNA function and potential RNA-mediated disease treatments.
To learn more about Sczepanski’s research, visit http://www.chem.tamu.edu/rgroup/sczepanski/.
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Contact: Shana K. Hutchins, (979) 862-1237 or firstname.lastname@example.org or Dr. Jonathan T. Sczepanski, (979) 862-3731 or email@example.com