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Fox Chase Cancer Center

Cancer Research: Amy Whitaker, PhD

Amy Whitaker, PhD, an Assistant Professor in the Nuclear Dynamics and Cancer Research Program at Fox Chase Cancer Center and Cancer Epigenetics Institute, 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).

“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.” While recent progress has been made in directly targeting a few specific KRAS mutations, patients quickly develop resistance to these new therapies.

“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.

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.

Amy Whitaker, PhD, displays crystals grown in the lab of protein:DNA complexes. Using a technique called X-ray crystallography the Whitaker Lab team will be able to determine key protein complexes that form on the KRAS promoter to activate production of KRAS. W. W. Smith Charitable Trust Research Project: “Regulation of oncogenic KRAS expression in PDAC via promoter DNA structural dynamics”

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