Cancer genes and tumors can evolve to resist treatment, making the ongoing discovery of new therapies essential in the fight against cancer. UNC Eshelman School of Pharmacy’s Chemical Biology and Medicinal Chemistry Division is a central hub for cancer therapeutics. Its faculty — more than half are UNC Lineberger members — are studying the chemical and biological mechanisms that promote cancer growth and persistence.
“We need better therapies,” said Ian Davis, MD, PhD, the Stuart H. Gold Distinguished Professor and chief of the Division of Pediatric Hematology-Oncology. “We need to prime the pump with fundamental discoveries and then keep our foot on the gas to keep them moving forward in the pipeline toward clinical trials.”
University Cancer Research Fund (UCRF) resources are vital to this work. The Fund helps support the Center for Integrative Chemical Biology and Drug Discovery at UNC, where staff members make proteins and help with compound management for multiple research labs. The UCRF also helped acquire some of the technologies in UNC’s high-throughput sequencing core, including state-of-the-art liquid handling platforms and genetic sequencers that are key resources for data-intensive research.
These technologies are used to read the genetic information in cancer cells for UNC and for outside research institutions, said Samantha Pattenden, PhD, associate professor of chemical biology and medicinal chemistry and the sequencing core’s managing director. She and Davis are using the sequencers as part of their longstanding collaboration on Ewing sarcoma, a rare but aggressive cancer that mostly affects bones and tissue of children and teenagers. Surgery, chemotherapy, and radiation are standard in the treatment of Ewing sarcoma. But chemotherapy’s toxic side effects are significant, and Ewing sarcoma often becomes resistant to treatment, leading to low survival rates.
Davis and Pattenden have invented an accelerated screening process that can simultaneously test thousands of potential compounds for efficacy against Ewing sarcoma. As part of the National Cancer Institute’s Experimental Therapeutics Program, and in collaboration with the National Center for Advancing Translational Studies, they are using this process on more than 120,000 molecules to identify compounds that affect the way that proteins and DNA interact, a key factor in Ewing sarcoma.
The main protein that drives Ewing sarcoma, EWS-FLI1, is hard to directly target with drugs, so studies seek to indirectly counteract its activity. Davis and Pattenden take advantage of the precise pattern of how DNA tightly or loosely interacts with proteins, a feature called chromatin accessibility. EWS-FLI1 fuels cancer growth by creating a characteristic pattern in DNA-protein interactions.
“Since we can’t target the oncoprotein, we are targeting chromatin accessibility,” Pattenden said, adding that compounds that show potential will undergo further study. “If we find a compound that closes the gap, we have a winner.”
The Davis lab also collaborates with the lab of David Drewry, PhD, professor at UNC Eshelman, to develop a compound that could activate destruction of the EWS-FLI1 protein in the tumor cells.
Taking a related approach, UNC Lineberger researchers are taking advantage of another potential weakness in Ewing sarcoma’s armor: ETV6, a protein that plays a role in cancer growth. Pengda Liu, PhD, associate professor of biochemistry and biophysics, and colleagues used custom-made DNA strands to develop a molecule that degrades ETV6 and suppresses Ewing sarcoma growth. Further studies will examine their molecule’s potential against other ETV6-driven cancers, such as leukemia and lymphoma.
NSD2, another cancer-driving protein, is implicated in several cancer types including pancreatic cancer, prostate cancer and multiple myeloma. Lindsey James, PhD, associate professor of chemical biology and medicinal chemistry, and colleagues have developed a promising new compound called UNC8732 that effectively degrades this protein, suppresses cancer cell growth, induces cell death and, in certain contexts, reverses drug resistance.
Protein degradation is a natural cellular process that breaks down damaged or misfolded proteins. Researchers used UNC8732 to hijack this process to enable degradation of NSD2 by recruiting a protein called FBXO22, an E3 ligase used to mark NSD2 for degradation.
Most protein degraders use two E3 ligases called VHL and CRBN, which somewhat limits the scope of protein degradation because some cancer cells don’t express these E3 ligases. UNC8732 is the first compound to recruit the FBXO22 E3 ligase, offering potential for more types of oncoproteins to be degraded.
“The more E3 ligases we know how to recruit, the more broadly applicable this therapeutic strategy is going to be, and the more cancer targets we can go after,” James said. “We are excited that companies have been inspired by our work and are using their vast resources to take what we’ve learned and move it closer to the clinic.”
Through the discovery of new cancer dependencies that can be therapeutically exploited, supporting critical equipment and technology, and fueling collaborations, UCRF helps open the spigot of new and innovative treatments for cancer.