Six researchers receive $3.5 million in grants from Kuni Foundation

Six researchers at Fred Hutchinson Cancer Center have received nearly $3.5 million in grants from the Kuni Foundation, bringing the foundation’s support for Fred Hutch to more than $12 million since 2020.

The proposed projects will evaluate circulating tumor DNA, or ctDNA, as a biomarker for Merkel cell carcinoma, or MCC; develop a therapeutic antibody to eradicate metastatic breast cancer; develop an oncolytic measles virus to treat B-cell non-Hodgkin lymphoma, or B-NHL; test the safety and feasibility of a novel combination therapy for retroperitoneal liposarcoma; and use multiomics and artificial intelligence to design personalized meningioma therapy.

“We’re excited about this latest round of bold, visionary projects and honored to support this vital work,” said Angela Hult, president of the Kuni Foundation. “The Pacific Northwest continues to drive impactful outcomes for cancer patients thanks to this group’s inventive collaboration.”

Recipients from Fred Hutch include Kevin J. Cheung, MD, associate professor in the Public Health Sciences and Human Biology divisions and associate professor in the Division of Medical Oncology at UW, and Brian Till, MD, associate professor in the Clinical Research Division and associate professor of medicine at UW.

Additional grants went to Paul T. Nghiem, MD, PhD, professor of dermatology and medicine and adjunct professor of immunology, oral health sciences and laboratory medicine and pathology at UW and holder of the George F. Odland Endowed Chair in Dermatology, and Lee D. Cranmer, MD, PhD, the Curtis and Elizabeth Anderson Endowed Professor in Sarcoma Research in the Division of Medical Oncology at UW, director of Sarcoma Medical Oncology and program director of the Bob and Eileen Gilman Family Sarcoma Research Program.

The Kuni Foundation also awarded a grant to neurosurgeon Manuel Ferreira, MD, PhD, UW Medicine’s chief of Neurological Surgery and holder of the Chap and Eve Alvord and Elias Alvord Chair in Neuro-oncology, and UW researcher Carolina Parada, MSc, PhD, an acting assistant professor in neurological surgery at UW who specializes in bioinformatics, computational biology and translational biotechnology.

Principal investigators for each project will collaborate with numerous colleagues across Fred Hutch and UW and in some cases with researchers at other institutions.

Blocking breast cancer metastasis at its origin

Cheung received a three-year, $900,000 grant to develop a therapeutic antibody to eradicate metastatic breast cancer by preventing cell death in the center of tumors.

The project is based on earlier work by Cheung and colleagues seeking to prevent metastatic breast cancer by asking, “Where do breast tumor cells metastasize from?” Their results suggest the answer is from the necrotic core of tumors that grow so fast they outstrip their nutrient and blood supply, leading tumor cells to separate from their neighbors and go elsewhere in the body.

“The result is a ‘flight’ response that occurs when the local environment becomes too toxic,” Cheung explained.

Importantly, necrosis triggers the selection of drug-resistant and highly metastatic cells that travel in clusters.

“It’s not just every tumor cell for itself,” he said. “Rather there are signals driving cooperation and supracellular coordination between cells. So, rather than thinking about these cells as individuals, think of them as an ecosystem of cells working together. From the time I started at Fred Hutch, my lab has been asking how does this happen? And how does a big clump of cells then get into the bloodstream? We’ve spent years trying to figure this out. That’s what led to the work that will be funded by this grant.”

Cheung and his team discovered that breast tumor cells next to central “dead zones” secrete a protein, angiopoietin-like-7, or A-7, that remodels the tumor microenvironment. It signals to tumor cells to grow past their nutrient limits, undergo necrosis and initiate metastasis. Turning off A-7 prevents necrosis and reduces the number of metastasizing cancer cells in the blood to nearly zero.

Powered by small donors, notably the Beth Caldwell Memorial Fund, Cheung collaborated with the Fred Hutch antibody development core to generate antibodies that might block A-7’s effects.

With the Kuni Foundation grant, the researchers will evaluate the 209 candidate antibodies they found, identify three that show promise and then test their efficacy. The top candidate will be tested in the lab in combination with three front-line standard-of-care chemotherapies for advanced breast cancer with the goal of selecting a combination to advance to clinical trials.

“I’m grateful for the patients and families who’ve supported our research and gotten us to this point. They are ultimately what’s driving us,” Cheung said. “The Kuni Foundation grant will be instrumental in us taking the next step, going from mechanistic, pre-clinical research to therapeutic development. This funding is really transformational.”

Could oncolytic virus therapy cure relapsed B-cell non-Hodgkin lymphoma?

Till was awarded $900,000 over three years to develop an oncolytic measles virus for use in treating B-NHL. The goal is to produce a safe, targeted, low-toxicity, “off-the-shelf” therapy that is affordable and can be given in a single infusion. Till hopes the therapy might even have the potential to be curative, including for some types of relapsed B-NHL that can’t be cured with standard chemotherapy-based treatments.

In oncolytic virus therapy, physicians harness a virus’s natural proclivity to enter and then replicate in host cells. By customizing a virus to seek cancer cells specifically, they can turn the virus into a weapon that selectively kills cancer from the inside out simply by making copies of itself. In addition, oncolytic virus therapy may trigger an immune response in the patient that helps destroy any cells in which the virus resides — and even noninfected cells if the immune system recognizes and attacks mutated tumor proteins.

Till and his team will use a virus derived from the measles vaccine, which has been safely given to billions of people for more than 50 years, modifying it to be tumor-specific. Their aim is to create a virus that will bind only to CD19 and CD20, which are target antigens on B-NHLs; will not be cleared by antibodies; will enter B-NHL cells widely throughout the body; and will have direct antitumor effects. They will also look for an antitumor immune response and any barriers to this response.

“There’s a lot of work going in in oncolytic virus therapy for solid tumors. But to my knowledge there are no clinical trials testing oncolytic virus therapy in lymphoma. Even in the preclinical space, there doesn’t seem to be much research going on,” said Till, who led the first published trial testing CAR T-cell therapy in lymphoma patients. He has extensive experience with viral vector design and preclinical optimization of immune-based therapies for lymphoma.

A challenge for the first researchers exploring a new class of therapy for a particular disease is the relative lack of funding sources — which is where an organization like the Kuni Foundation comes in.

Before they’re willing to provide financial support, "traditional funding mechanisms, like the NIH, like an R01 grant, or even some other foundations, want the project to be more established with more data already,” Till said. “To get a good idea off the ground, somebody has to take a risk and fund a project that doesn’t already have a lot of data behind it — high-risk, high-reward projects. Otherwise, they might not ever happen.”

A possible ‘quantum leap’ in Merkel cell carcinoma surveillance

Nghiem received a two-year $391,000 grant for a clinical trial to validate ctDNA as a biomarker for MCC, which has a high recurrence rate. UW Medicine’s head of dermatology, Nghiem is the most published author in the MCC field. He is an affiliate investigator in the Clinical Research Division, as well as director of the Fred Hutch Skin Oncology Clinical Program.

In ctDNA testing, a blood sample is used to detect cancer-specific DNA shed by a patient’s tumors. Tumor-specific DNA mutations are identified by comparing whole genome sequencing of the patient’s “normal” DNA to mutations found only in their tumor. So, the test is patient specific by necessity.

Along with colleagues at Stanford, Nghiem has already completed a pilot study of 125 patients that showed a ctDNA blood test has high sensitivity for identification of MCC tumors larger than 0.5 centimeters and often detects recurrent disease several months before imaging scans, currently the primary surveillance method. In addition, it provides a quantitative real-time readout of MCC disease burden because ctDNA levels in the blood strongly correlate with tumor size.

The preliminary data suggests ctDNA provides a “quantum-leap” improvement in sensitivity over scanning, the researchers wrote in their grant proposal. Now, Nghiem and his collaborators plan to enroll 500 patients in a multicenter study they hope will not only validate ctDNA for MCC surveillance but revolutionize care worldwide.

Researchers will check for ctDNA at a patient’s office visit prior to the start of treatment and every three months thereafter for several years. Patients will also have imaging studies according to National Comprehensive Cancer Network guidelines.

Earlier detection of MCC recurrence allows physicians more time to intervene and hopefully improve patient outcomes.

“It gives us more ‘shots on goal,’” Nghiem said. “No single approach to treating recurrent MCC works in everyone. Earlier detection gives us more months in which to try plan B or plan C while the patient is still well enough.”

“The Kuni Foundation wants to make a difference for patients sooner rather than later, and they want to get things going that will have a significant downstream impact. I think this study meets both of those criteria,” he said. “I believe it will change management as soon as we publish the results.”

Fred Hutch/UW will be a lead site for the trial along with Stanford. Additional sites will include Dana-Farber Cancer Institute, Moffitt Cancer Center, University of California San Francisco and Northwestern University.

The difference between putting an idea on the shelf and bringing it to sarcoma patients

Cranmer received a three-year $300,000 grant for a Phase 1 clinical trial of a novel combination of abemaciclib and radiation therapy for advanced retroperitoneal liposarcoma. He is a professor in the Clinical Research Division.

RLS can be difficult or impossible to remove completely with surgery because by the time of diagnosis the tumors are often large and involve critical structures in the abdomen. As a result, most recurrences happen locally, in the retroperitoneal space, rather than at distant sites in the body. Cranmer hopes the combination of abemaciclib and radiotherapy may improve outcomes by enhancing local control. But before he and others can test this hypothesis, they first need data on the safety and feasibility of the approach.

Despite completing initial institutional scientific review and having a finalized Phase 1 trial protocol, funding was not forthcoming. Pharmaceutical companies and other potential partners expressed interest in supporting the next step, a Phase 2 randomized clinical trial. But they held back on funding the small pilot study needed to generate crucial preliminary data that could justify further investigation.

“The Kuni Foundation was crucial in making this project happen, in essence providing the seed so we can demonstrate that this approach is safe and feasible and then conduct a much larger national study, which is already in the development stages. Without them, we would have had to just put this idea on the shelf,” Cranmer said. “I’m so thrilled that the Kuni Foundation came through for patients facing this devastating illness.”

In the study, nine to 18 patients will receive abemaciclib along with radiation therapy before undergoing surgery to remove their tumors. Abemaciclib, approved to treat breast cancer, is expected to have direct anticancer effects against RLS, arresting tumor growth, and potentially to sensitize RLS cells to radiation therapy, which could help shrink tumors, making them easier to remove with clear margins. Successful initial surgery correlates with better outcomes over time and less likelihood of recurrence, and it limits other complications, greatly reducing surgical comorbidities.

By tracking subjects’ symptoms along with results of objective measures, such as blood and urine tests and imaging scans, researchers will attempt to identify the maximum tolerated dose of abemaciclib — and the recommended dose for the planned national Phase 2 trial that would enroll many more patients and confirm the therapy’s efficacy.

Personalized meningioma therapy powered by Artificial Intelligence

Ferreira and Parada were awarded $990,000 over three years to develop precision therapy for pediatric and adult meningioma patients using multiomics and AI.

Meningiomas are the most common primary central nervous system tumor. They are usually benign, but about 20% unexpectedly become clinically aggressive even after total resection. While surgery and radiation are usually effective for benign tumors, there is no standard of care for more aggressive disease. Ferreira and Parada hope to fill this gap with personalized kinase inhibitor therapy.

They will evaluate 3D slices of an individual’s tumor by multiomics, revealing a wide array of information about the tumor’s unique characteristics, molecular complexity and microenvironment. Multiomics can identify disease drivers that can be targeted by kinase inhibitors.

AI will screen for combinations of kinase inhibitors already approved for other diseases by the Food and Drug Administration that could be repurposed for meningioma and possibly reverse the patient’s disease. Dose and drug combinations will be tested against the patient’s own tumor cells in the lab. This step relies on work by Taran Gujral, PhD (a previous Kuni Foundation awardee), to keep cells in tumor slices alive for weeks in a laboratory setting and observe how they respond to different medicines.

If successful, the process will result in a customized recommendation of kinase inhibitors that the treating oncologist could then offer to the patient when surgery and radiotherapy are no longer options, rather than having to guess which drugs might be effective.

Personalized therapies may be an ideal treatment approach in meningiomas, said the researchers, because omics data has revealed molecular heterogeneity between meningiomas. In other words, what works for one patient may not work for another because their meningiomas differ.

“In research, we often talk about taking therapies from ‘bench to bedside.’ This project is sort of ‘bedside to bench back to bedside,’” said Ferreira, who is co-director of Skull Base and Minimally Invasive Neurosurgery, surgical director of the Multi-Disciplinary Pituitary Program and professor and vice chair of neurological surgery, UW.

“It’s very unique for a foundation to specifically seek projects pursuing an approach, like ours, that’s not already established,” Ferreira added, “but some of the greatest advances have come from this type of research.”

The researchers will start with surgical specimens from adult and pediatric patients collected at UW Medical Center and additional pediatric specimens from Seattle Children’s Hospital and Oregon Health & Science University. By the third year of funding, they hope to include community-based hospitals in Washington and Oregon, extending their precision-therapy platform throughout the Pacific Northwest and later to Alaska.

Since 2020, Fred Hutch principal investigators working at Fred Hutch and UW Medicine have received more than $12 million from the Kuni Foundation, supporting 28 different projects.

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.