PHILADELPHIA (January 22, 2024) — Amy Whitaker, PhD, an Assistant Professor in the Nuclear Dynamics and Cancer Research Program at Fox Chase Cancer Center, recently received a $125,000 grant from W.W. Smith Charitable Trust to evaluate the regulation of KRAS gene expression in pancreatic ductal adenocarcinoma (PDAC).
The W.W. Smith Charitable Trust is a private foundation focused on ensuring basic human needs, supporting low-income students through scholarship grants to accredited colleges and universities, and enabling basic medical research in the areas of heart disease, cancer, and AIDS.
“PDAC is very aggressive and largely not responsive to current treatment options, making it a clinical challenge to treat,” Whitaker said. “Mutations in the KRAS gene change the KRAS signaling protein’s function and promote PDAC tumor growth.”
Researchers have been studying oncogenic KRAS proteins in the hope of developing drugs that block their cancer-causing activities, but progress has been slow. In fact, for years, KRAS was considered to be unresponsive to drugs. However, recent progress has been made in targeting a few specific KRAS mutations such as KRASG12C. Unfortunately, these are not the same mutations commonly found in patients with PDAC.
In the project funded by this grant, Whitaker will attempt to discover alternative ways to treat KRAS-mutated PDAC by targeting KRAS indirectly.
“It remains an urgent and unmet need to target oncogenic KRAS in PDAC. The indirect targeting of KRAS, through reducing its expression, offers an exciting alternative, as it would be applicable to all subtypes,” Whitaker said.
One way to reduce expression is by disrupting interactions between regulatory proteins and regions of the DNA that promote production of KRAS.
Whitaker said KRAS production depends on the folding of a DNA structure called a G-quadruplex (G4), or “knot,” in its gene promoter. “In response to the folded motif, regulatory proteins bind the DNA knot to promote KRAS production.”
Whitaker hopes to determine what controls the folding of this DNA knot and to establish the key protein complexes that form on the DNA knot to activate production of KRAS.
To do this, she will use a combination of cell-based gene expression assays, biochemistry data utilizing biologically relevant double-stranded G4-DNA substrates, and innovative techniques such as single-molecule fluorescence microscopy capable of simultaneously observing G4 structural dynamics — such as DNA folding and unfolding — and protein-DNA interactions.
These findings could eventually aid in rational drug design for targeting KRAS gene expression through disruption of the key interactions, and, ultimately, provide new treatment options for KRAS-mutated PDAC.
In addition, to directly address the health disparities in PDAC, a disease where Black patients have a 50% to 90% higher incidence compared with other racial groups, future work translating these findings will include diverse study samples and partnerships with advocacy groups such as the Pancreatic Cancer Action Network that work to reduce these disparities.