Rare cancer researchers find promising target in fibrolamellar cancer

Challenges of rare cancers

Diagnosed at age 22, David Burch of Olympia, Washington, now 42, has been dealing with FLC for over two decades. Like many FLC patients, he was initially misdiagnosed with the more common type of liver cancer (hepatocellular), which caused the longtime Costco employee some grief.

“The questions made me feel like it was my fault,” he said. “I was just 22 and was repeatedly being asked about the amount of alcohol I drank, what kind of sexual experiences I had. At the time, it was thought the only way to get liver cancer was to have cirrhosis or hepatitis A or B. I was told it was a death sentence and that they would never find a cure. I was told I probably wouldn’t have kids due to the chemo they had me on.”

After a consultation with Fred Hutch’s William Harris, MD, though, Burch decided to change providers.

“I realized I was not getting the care I needed,” he said. “He really knows this stuff. I understand now that the limited information that is out there about fibrolamellar is not regularly available to all the different doctors. So I’m not blaming any doctor or hospital. But I do blame the circumstances; we need to get more information out there about FLC.”

After transferring his care, things changed dramatically.

“Within the first few visits, I knew more about my cancer than ever,” he said. That’s also when he began connecting with other patients and with researchers working to solve FLC. He attended a seminar at Fred Hutch in 2018 and learned about the urgent need for tissue samples and new treatments for this rare cancer. He began meeting annually with other FLC patients and caregivers.

Somewhere in there, he also learned that the chemotherapy had not sterilized him. Burch now has two kids.

Since his diagnosis, Burch has gone through more than a dozen surgeries, multiple rounds of chemotherapy and a handful of radiation or radiofrequency ablation treatments. Most recently, he had to have his left lung removed due to a metastatic recurrence of the FLC.

But he continues to learn about the disease, to help others who’ve been diagnosed with it and to be encouraged by the increasing amount of research.

“When I was first diagnosed, it didn’t feel like anyone was working on this,” he said. “I didn’t see the first real article about FLC until six or seven years after I was diagnosed. Until then, I’d Google and see things like ‘You’re going to die in six months.’ Hearing from doctors and scientists has given me hope.”

Creating pre-clinical models … and hope

Hope isn’t the only thing that’s been missing for many of these patients and the researchers trying to help them. As with many rare cancers, there’s also a lack of pre-clinical models such as cell lines and mouse models for FLC, primarily due to the paucity of patients; fibrolamellar is so rare that only one or two people in a million are diagnosed. Scientists use these tools to test out potential therapies on cancer cells living in a dish — or on a preclinical model, like a mouse.

“When we started working on this cancer, there was one model which had been developed by researchers about 15 years ago,” Gujral said. “That’s the model that everyone uses, but when you just have one model it can be concerning because all your findings are based on a single, patient-derived model.”

So, the team created not just a new cell line for fibrolamellar, but also new PDX models or patient-derived xenografts (mice with “human” tumors). While it may sound easy, it’s a major feat requiring a close collaboration between the researchers in the lab and oncologists, surgeons, pathologists and, of course, patients who’ve been diagnosed with a particular rare cancer.

Freshly resected tumor tissue is essential for the process, so timing, communication, coordination and logistical precision are key.

Gujral began collaborating with Seattle Children’s pediatric surgeon Riehle and Raymond Yeung, MD, a liver cancer surgeon and founder of the Liver Tumor Clinic at UW Medical Center – Montlake, to identify FLC patients, stockpiling their fresh tissue samples.

“They would see maybe two or three patients a year,” he said. “Sometimes less. We were able to get fresh specimens from their surgical resections from six or seven patients [with consent, as part of the IRB-approved study] and were able to generate the models from that. That was our key contribution to the paper in Cancer Discovery.”

Symposium highlights rare cancers

Researcher John D. Scott, PhD, FRS, a professor and chair of pharmacology at the University of Washington and one of the collaborators on the Gut paper, was one of many speakers featured at Fred Hutch’s 3rd Rare Cancers Research Symposium, held April 21.

“Taran’s talent in combining standard pharmacology with artificial intelligence allows us to make great strides forward in cancer chemotherapy,” he said.

The symposium, which included rare cancer researchers and advocates from around the country, provided a forum to share challenges, insights and new investigative efforts within pediatric immune system-related malignancies; vaccine development for Kaposi sarcomas; myeloid disorders; rare brain tumors; Ewing sarcomas; germ cell tumors and much more.

Marshall Thompson, PhD, president of the Rare Cancer Research Foundation, spoke about accelerating cures through patient-powered collaborations and advocacy.

“The stuff we talk about is exactly what the TRACER program is trying to do,” he said, referencing Gujral’s new rare cancer research initiative. “We’re trying to build infrastructure to allow more people to work faster and more effectively on advances for rare cancer. There’s no TCGA — The Cancer Genome Atlas — for rare cancers.”

Not yet, anyway.

The RCRF has created a biobank for rare cancer tissue called Pattern.org so patients (and their doctors) can donate living tumor tissue to researchers all over the country.

“We’ll contact the surgical suite and the medical oncologist and send a kit anywhere in the U.S.,” Thompson said. “We’ll facilitate all the bio-logistics so samples can be shipped the next day to partner researchers like TRACER or to our biobank or to viable cryopreservation. We’ll use it to build model systems, cell lines and organoids that everyone can access in the future.”

So far, Thompson said the organization has generated 60 models including “some of the first cell lines for several rare tumor types.”

Advocacy and collaboration key to success

Thanks to the addition of these new cell lines and preclinical models — and to the spotlight advocate organizations are shining on the disparities these patients suffer — the rare cancer research picture is finally shifting.

“It’s very hard to get funding from government sources when you have no model, when it’s high risk,” Gujral said, adding that pharmaceutical companies usually focus on finding therapies for cancers with more patients — and more potential for profit. “Until a few years ago, there wasn’t a single grant for FLC for our group, but now we’re getting models, getting data, building programs and starting to share major findings.”

Gujral credits advocacy organizations like the Fibrolamellar Cancer Foundation, which helped support his early research.

“Having a model of FLC significantly improves our ability to secure funding,” he said. “The Foundation is the force behind moving research from the lab to the clinic. They’re dedicated to funding early research and to curing this cancer.”

Gujral said there are currently two FLC clinical trials in the works — one in the U.S. and one in Europe. He hopes to launch a new one soon to test out PLK1 inhibition.

“A clinical trial with patients is the next step,” he said. “We’ve demonstrated proof of concept in different models and different patients. The next step is getting a clinical trial going although that will be a challenge.”

How does that sound to Burch, the FLC patient?

“I am so excited to see things like this TRACER group,” he said. “When I was first diagnosed, there was nothing really being done with fibrolamellar or other rare cancers. And researchers were very guarded about the discoveries that were being made. It’s really cool to see this collaboration. I was originally told I had three years to live but thanks to Fred Hutch and UW, I’m now going on 21 years.”

Funding for these studies was provided by the Fibrolamellar Cancer Foundation, Alex’s Lemonade Stand Foundation for Childhood Cancer, Bertarelli Rare Cancers Fund, American–Italian Cancer Foundation, the Chen Institute MGH Research Scholar, the National Institute of Health/National Cancer Institute, The Novo Nordisk Foundation, the U.S. Food and Drug Administration, the Department of Defense, the Brotman Baty Institute. The work was also supported by the Comparative Medicine, Preclinical Modeling and Cellular Imaging Shared Resources of the Fred Hutch/University of Washington Cancer Consortium NIH/NCI.