$5.25M from the Kuni Foundation propels innovative adult oncology research

Principal investigators working at Fred Hutch Cancer Center and UW Medicine secured $5.25 million in grants from the Kuni Foundation for a diverse lineup of projects to advance our understanding of tumor regression and improve care for an array of adult cancers, including by reducing the cost of therapy.

The projects will explore why some cancerous tumors shrink or disappear without treatment; test whether the immunotherapy nivolumab works when given less often and at lower doses; investigate what drives disparities in breast cancer screenings; evaluate a method to detect and treat liver tumors earlier by selectively delivering radiation to tumor cells; and lay the groundwork for personalized hyperthermic peritoneal chemotherapy (HIPEC) for cancer on the lining of the abdomen. Each awardee will receive $1,050,000 over three years.

“The Pacific Northwest is a hub for bold, visionary cancer research, and we’re inspired by the inventive work happening at Fred Hutch and UW Medicine,” said Angela Hult, Kuni Foundation president. “We’re honored to help accelerate the impactful work of these cancer researchers and their exciting efforts to improve access and outcomes for underserved communities and yield new, effective treatments in service to a cure.”

This year’s grants bring the Kuni Foundation’s total support for Fred Hutch principal investigators working at Fred Hutch and UW Medicine to more than $17 million since 2020. 

Recipients from Fred Hutch include David M. Hockenbery, MD, professor in the Translational Science and Therapeutics, Human Biology and Public Health Sciences divisions at Fred Hutch and professor in the Division of Gastroenterology at the University of Washington; and Shailender Bhatia, MD, professor in the Clinical Research Division at Fred Hutch and professor in the Division of Hematology and Oncology at UW. 

Additional grants went to Fred Hutch and UW Medicine physicians Christoph I. Lee, MD, MS, professor of radiology at UW; James O. Park, MD, FACS, director of the Liver Tumor Clinic for UW Medicine and professor of hepatobiliary and pancreatic surgical oncology at UW; and Jeremy Sharib, MD, assistant professor of surgery at UW.

The Kuni Foundation awarded additional grants to projects from the UW Medicine Cancer Vaccine Institute and UW College of Engineering.

Unraveling a marsupial medical mystery

A feisty marsupial from 8,000 miles away may have put Fred Hutch researchers on the path to developing a therapy that could one day make tumors disappear. 

Tasmanian devils, found only on an island off Australia’s southeast coast, are afflicted with a transmissible form of cancer, called devil facial tumor disease (DFTD). It’s thought to spread between the animals through bites. Individual devils don’t simply have the same type of cancer, like two people who both have lung cancer; they have the same cancer, which spreads from one devil to another through direct contact. 

By capturing affected devils, sampling their tumors, releasing them and then later capturing them again, researchers found something surprising: Over time, the lumpy facial tumors vanished from a small subset of animals. 

Spontaneous regression like this happens in human cancers too — rarely — with tumors shrinking or melting away without any intervention. But this is difficult to study. 

“Usually in cases like this, a doctor diagnoses someone, samples their tumor, confirms it’s cancer and schedules them for surgery. But then when they go to do the surgery, they can’t find the tumor. It’s gone but was never treated,” said Hockenbery. 

“How could this happen? Unfortunately, you can’t really look at the cancer itself for answers. Every cancer in a person is different because it develops from a different individual’s cells. Not so in the Tasmanian devils. They have the same cancer.”

Hockenbery and his collaborators studied samples from eight devils whose tumors had regressed and discovered an interesting link. Tumors in seven of the animals had the same mutation in part of the RASL11A gene. The mutation was absent in a control group whose tumors kept growing. 

The team’s early experiments, supported by a previous Kuni Foundation grant, showed that DFTD cells expressing RASL11A are “supercompetitors.” Though these cells grow slower than the rest of the tumor, they somehow kill neighboring tumor cells that lack RASL11A expression. The researchers showed a similar effect by introducing a similar human gene to human colon cancer cells in the lab. 

With the new three-year grant, Hockenbery will delve deeper into what’s happening and how scientists might harness this phenomenon to create new treatments. His team will measure how well RASL11A+ cells outcompete RASL11A- cells in lab experiments and investigate what makes the RASL11A+ cells winners. They will also test whether gene therapy can make colorectal cancer cells express RASL11A, inducing tumor regression. 

“The Kuni Foundation is on the lookout for projects that seem to have promise but would not necessarily be funded by the National Institutes of Health — such as studying an animal that only exists in Tasmania — and we’re really grateful for their help. Ideally, this grant will be a stepping stone to help us get enough data to make a strong argument to the NIH for future support,” said Hockenbery.

How good is a therapy that’s too expensive to use?

At the standard dose and frequency, the immunotherapy drug nivolumab costs about $210,000 per year for just the drug alone, not including other fees associated with care. Nivolumab is used to treat many types of cancer, and this price tag puts it out of reach for some patients, like those who are uninsured, are denied coverage by their insurance or reside in parts of the world where resources are more constrained. It is prohibitively expensive in low- and middle-income countries, such as Uganda, where Fred Hutch partners with the Uganda Cancer Institute (UCI) to operate the UCI-Fred Hutch Cancer Centre, a research, training and outpatient care facility. 

Physicians may be able to slash the cost of nivolumab by as much as 98% if a much lower dose given less often proves effective. Bhatia and his collaborators hope to prove just that. With support from the Kuni Foundation, they will conduct a phase 2 clinical trial at UCI testing a markedly lower-dose plus reduced-frequency strategy. The study will make nivolumab available to patients who would otherwise not have access to the drug at all. 

People in the study will receive a 40-milligram (mg) dose every 12 weeks. The current standard is a 480-mg dose every four weeks. Besides costing less, the study strategy means less-frequent trips to the clinic to get the drug, which is given by infusion. This is especially important for patients in rural communities far from a treatment center. Researchers will track the percentage of people who respond to the study regimen, how much their tumors shrink and how long the response lasts.

How excited is Bhatia about the potential?

“On a scale of zero to 10, I’d say 15 or 20! Fred Hutch has been on the leading edge of the immunotherapy revolution for many years. But it’s also been clear that while these drugs can have such an incredibly positive impact on our patients, the vast majority of the world doesn’t have access to them because they’re so expensive. If this approach pans out, it could save millions of lives across the globe,” Bhatia said.

His earlier work, some of which was also supported by the Kuni Foundation, provides reason for Bhatia’s enthusiasm. For example, Fred Hutch physicians have been offering reduced-frequency nivolumab once a patient is doing well on the standard regimen. For other patients, they’ve given a lower dose to reduce the risk of severe and prolonged side effects. Lower doses appear very similar to the standard dose in terms of effectively hitting their target on the immune cells, lasting in the patients’ blood stream for several months and having the intended immune response against the cancer.

“We certainly appreciate the generosity of the Kuni Foundation in supporting a project like this that would not be funded by the pharmaceutical industry because it means using less of their product,” Bhatia said.

Bhatia, the principal investigator, or PI, for the study, also directs the Fred Hutch skin and kidney cancer clinical programs. He’ll be collaborating with co-PI Lisa Tachiki, MD, medical oncologist at Fred Hutch and assistant professor in the Division of Hematology and Oncology at UW, who led much of the preliminary work; administrative PI Manoj P. Menon, MD, MPH, associate professor in the Vaccine and Infectious Disease and Clinical Research divisions at Fred Hutch, associate professor in the Division of Hematology and Oncology at UW and holder of the Scripps Endowed Professorship in Hematology; and Fred Machyo Okuku, MBChB, MMed, lead investigator at the UCI.

NW-SCORE builds capacity to understand breast cancer disparities

Timely breast cancer screenings and diagnostic services can make a real difference in breast cancer outcomes. But not all people receive equitable care or get timely and accurate results from the care they do receive, and the reasons can be complex. Individual-level factors, like insurance status, play a role. Neighborhood-level factors and facility-level factors can drive disparities too. 

The Northwest Screening and Cancer Outcomes Research Enterprise (NW-SCORE), directed by Lee, aims to better understand these complexities so that imaging facilities and policymakers in Washington state and Oregon can improve health equity, especially for people who have traditionally been underserved. NW-SCORE already collects data from more than two dozen facilities. With support from the Kuni Foundation, the group will recruit another five to seven facilities that mainly serve rural or low-income people.

“We know certain women have worse outcomes related to breast cancer screening, but we don’t know exactly which factors lead to these worse outcomes. One hypothesis is they have challenges accessing quality care. For example, having competing priorities in life and then needing to drive long distances to get screenings or diagnostic work-ups may be leading to delayed diagnoses and disparities in cancer outcomes,” Lee said.

The project’s goal is to increase the capacity of NW-SCORE to include screening data from more facilities that screen underserved populations and then determine which factors at the neighborhood or facility level matter.

“The amazing thing about the Kuni Foundation is that they allow funds to be used for capacity building and adding to an established research program, unlike federal funding that’s focused on very specific scientific aims. In this way, the Kuni Foundation allows for even more innovative research,” said Lee.

The research team will geocode each patient’s residential location — a way to link each woman with neighborhood-level social determinants of health, such as levels of racial segregation, income, employment, housing quality and rurality. The team will also consider factors that might differ by facility, like what imaging technologies they have and how well they follow up on abnormal screening results. This data will help set regional benchmarks, such as the average time to diagnosis after abnormal screening, so that researchers can compare facilities and find ways to improve performance at lower-performing facilities.

Using NW-SCORE data, the researchers will also evaluate whether commercially available artificial intelligence, or AI, tools can help low-performing facilities interpret mammograms and accurately identify women who need timely follow-up with the goal of earlier cancer diagnosis and intervention. A previous Kuni Foundation grant allowed NW-SCORE to build the infrastructure to support evaluating AI tools for mammography.

A potential paradigm shift in liver cancer diagnosis and treatment

Liver cancer is the third most deadly cancer, and its numbers are rising while all other cancers are decreasing in incidence. With today’s standard imaging techniques — computed tomography (CT) and magnetic resonance imaging (MRI) — physicians can only diagnose cancerous liver tumors larger than 1 centimeter across. This can mean missing some cases of liver cancer entirely, at least until tumors grow larger, or doing surgery to remove a visible tumor without knowing other smaller tumors already exist and will cause a recurrence soon. 

A different imaging technique has the potential to improve diagnosis dramatically by pairing an antibody that seeks cancer cells with a radioactive tracer. This could reveal even very tiny liver cancers on a targeted positron emission tomography (PET) scan. The same antibody could also deliver therapeutic levels of radiation directly to liver cancer cells to treat the disease, a welcome prospect given that current treatments don’t work well for most patients.

Park and his team have developed an antibody that targets glypican-3 on most liver cancer cells. With previous support from the Kuni Foundation, they’ve made a version that can be used safely in humans. With the new three-year grant, they will further develop and test the antibody, moving it one step closer to clinical use.

“People with hepatitis B, hepatitis C or cirrhosis, which could be related to obesity and fatty liver disease or to alcohol use, are at risk for liver cancer. They need to undergo surveillance to check for possible tumors. This is currently done with ultrasound and blood tests. If we see a mass on the ultrasound, then we follow up with CT or MRI,” Park said.

Similar methods are used to check people with known liver cancer who have had treatment.

“If our antibody-targeted immuno-PET approach comes to fruition, it will be a real game changer,” Park said. “We’ve already shown our platform can detect tumors 0.3 millimeters in diameter or even smaller.”

Ideally, once liver cancer cells are found, the glypican-3 antibody could then be used to carry a payload of a high-energy radiation to these cells, killing them on contact. This type of treatment is called radioimmunotherapy (RIT).

To move their approach forward, the research team will work on making a glypican-3 antibody fragment that works as well as the whole antibody they developed; for example, it will need to bind just as well to liver cancer cells. Antibody fragments can have certain advantages over whole antibodies. Fragments may shorten the time that patients must wait between getting the antibody-radiotracer combination and having a PET scan. Also, antibody fragments may be able to enter the center of cancers more easily, improving the effects of RIT. 

“There’s stigma around liver cancer because of its association with hepatitis C, and thus injection drug use, or alcohol use. The resulting health inequity is even more striking in minority and underserved populations. There’s not as much enthusiasm around funding liver cancer as there is for some other cancers. I am extremely grateful to the Kuni Foundation for seeing beyond the stigma and seeking to address these unmet needs,” Park said. 

Moving toward precision medicine for peritoneal cancer

For most people with cancer, chemotherapy means getting an intravenous infusion of medicine that travels through the blood to reach cancer cells throughout the body. But if cancer has started on the peritoneum, the lining of the abdomen, or if it has spread there, typically from a nearby organ like the colon or appendix, chemotherapy could mean something quite different. 

Patients with peritoneal surface malignancies commonly have conventional systemic chemotherapy followed by surgery to remove as much of their cancer as possible (cytoreductive surgery, or CRS). If the surgeon can achieve complete cytoreduction, they may take an extra step of giving the patient HIPEC. 

In HIPEC, liquid chemotherapy medicines are warmed, put inside the abdomen through a tube, circulated for 1-2 hours and then drained before the surgeon closes the incision. The heated chemotherapy treats abdominal surfaces and kills stray cancer cells that might be left behind after surgery.

“This is a fairly blunt tool: pretty aggressive surgery plus chemo at the time of surgery that — while effective in the best circumstances — is an older agent. It’s not something we generally use systemically because of toxicity issues. We really have not innovated on it in a long time. There’s a lot of opportunity to develop the concept of precision medicine in relation to HIPEC and peritoneal cancer,” Sharib said. 

With the Kuni Foundation grant, Sharib and his team hope to show they can use tumor cells from a patient’s biopsy to identify medicines likely to be effective against that particular patient’s tumor. This information would allow the surgeon to personalize the patient’s HIPEC treatment. 

For their approach to one day become a reality, the researchers will test whether they can use a patient’s tissue to grow a model of the patient’s tumor in the lab and then treat the lab-grown tumor cells with different medicines, seeing how the cells respond. They will also use an AI-based drug-screening platform, developed by Fred Hutch scientist Taran Gujral, PhD, to match the characteristics of the patient’s tumor cells with medicines in a large drug library. The idea is that this would inform which medicines to test on a patient’s cells.

It’s normal to have about six months between a patient’s biopsy and their CRS-HIPEC. The researchers believe this would be plenty of time to complete the steps to select the best HIPEC agent for that individual. 

As part of their project, the team will also investigate whether they can find circulating tumor DNA (ctDNA) — evidence of current or prior cancer cells — in fluid collected after washing out the abdomen during surgery for cancers that may spread to the peritoneum. If they can find ctDNA, this might help physicians determine who is at risk for peritoneal disease. This could help them decide if HIPEC is worthwhile in patients with gastrointestinal tumors but no visible spread to the peritoneum. 

“This work fits well into the high-risk/high-reward category. There’s not a lot of background research on this particular platform in this disease population, so it’s important to have an organization like the Kuni Foundation with the flexibility to support efforts like this. Our goal is to turn this project into a clinical trial to actually treat patients — to have it be a truly translational effort,” Sharib said.

Based in Vancouver, Washington, the Kuni Foundation is committed to funding innovative cancer research that promotes early detection, enhances treatment and improves outcomes. They focus on underfunded areas of research, including rare cancers, and emphasize collaboration among individuals and institutions as well as accessibility to clinical trials for underserved communities.