Seeking targeted treatments for pancreatic cancer

Pancreatic cancer rates are rising. Pancreatic ductal adenocarcinoma, the most common and most aggressive kind of pancreatic tumor, is on track to become the second-leading cause of cancer-related death in the U.S.

The increase in incidence of pancreatic cancer is a big problem on its own. But it’s compounded by another problem, said pancreatic cancer researcher Dr. Nithya Kartha.

“The second issue is the therapy hasn't really kept up with that [increase],” said Kartha, a postdoctoral fellow in the lab of pancreatic cancer expert Dr. Sita Kugel at Fred Hutchinson Cancer Research Center. While prognosis varies by tumor stage, overall, only 9% of patients with pancreatic ductal adenocarcinoma can currently expect to live five years past diagnosis.

Earlier this year, Kartha received a fellowship from the American Cancer Society to seek out targeted treatments for the most aggressive subtype of pancreatic cancer. While targeted treatments have helped increase survival for patients with lung cancer, all patients with pancreatic ductal adenocarcinoma currently receive the same chemotherapy regimen.

“The goal [of the Kugel Lab] is to identify biomarker profiles that we could use in the clinic,” Kartha said. “So, when we get a sample of a patient’s tumor, we can say, ‘Based on these markers, this treatment will work better for you.’ There’s a lot of room for research in that area.”

On the hunt for tailored treatments

Targeted cancer therapies often zero in on genetic differences the set individual patients’ tumors apart from each other. But for the most part, pancreatic tumors share a common set of cancer-driving mutations, making it difficult to create tailored treatments based on their genetics, Kartha said.

Instead, researchers found that they can group tumors into clinical subtypes based on which genes are turned on or off, and how strongly they’re turned on, or expressed.

The different gene expression profiles correlate with patients’ prognosis. The profile with the worst prognosis is the basal or quasi-mesenchymal type. In previous work, Kugel’s team found that basal-type pancreatic tumors were uniquely sensitive to a type of drug that alters their ability to turn genes on and off.

The three-year ACS fellowship will allow Kartha to dig into what makes basal tumors so sensitive to this type of drug, and further test how well it works against tumors in preclinical systems that mimic tumor biology — important steps toward moving Kugel’s discovery to the clinic.

“The goal is to exploit this vulnerability that these cancer cells have created, even though they're more aggressive,” Kartha said.

Countering drug resistance

As part of this work, Kartha will also explore how pancreatic tumors develop resistance to targeted drug treatments.

“You would expect that when a therapy is more targeted, the [tumor] cells will more quickly find a way to adapt,” she said. When a drug acts with pinpoint precision, even a small change in its target could allow a tumor to escape.

By studying this problem now, Kartha hopes to uncover the molecular pathways that tumors follow to resist the drug — and find ways to head them off.

The idea is to “get ahead of it, then see if there's a way we can hit [the drug-resistant tumor] with another drug,” Kartha said. Hopefully, this will give oncologists a full toolkit of tailored treatments for pancreatic cancer, allowing them to better treat drug-resistant tumors or perhaps prevent resistance to begin with.

These studies are “also a good way of uncovering new biology,” she said. “Even just to see how they would adapt to something like this is going to reveal something new.”