Eight Fred Hutch teams win Evergreen Fund awards

A return winner

Researchers whose projects made progress are eligible to come back to the Evergreen fund for more assistance, and this year Jim Boonyaratanakornkit, MD PhD, is the recipient of a second Beyond Pilot grant to continue work that was boosted with a similar grant in 2020.

“We are extremely excited and grateful for the opportunity to build on a really important and unexpected finding that arose out of our first Evergreen-funded project,” he said.

This 2020 grant set him on a course to develop a laboratory-designed antibody, a type of immune protein, capable of blocking several different respiratory viruses. This year, his Beyond Pilot grant will help him and his team to enhance existing laboratory-designed antibodies, including those developed with the help of that first grant. These immune proteins can stop two dangerous common viruses that are threats to cancer patients who are immune compromised in the weeks after bone marrow transplants.

One of those pathogens is RSV, or respiratory syncytial virus, the currently notorious culprit behind this fall’s serious outbreak among children. A second is human metapneumovirus, or HMPV, a related virus that also can cause pneumonia in youngsters.

RSV and HMPV each pose a particularly serious threat to patients who are recovering from bone marrow or blood stem cell transplants. Up to 40% of such patients who develop pneumonia from these viruses die within three months. With the Evergreen grant, Boonyaratanakorkit and co-investigator Justin Taylor, PhD, will test modifications to improve the performance and effectiveness of laboratory manufactured, or monoclonal antibodies, including their dual acting protein they call MxR. If they can further boost MxR’s and similar antibodies’ effectiveness in preclinical studies and show these modified antibodies work with fewer doses and smaller dose sizes, they believe they will have drug candidates that will save lives and be attractive to drugmakers with the wherewithal to bring them to market.

A potential blocker of breast cancer metastasis

Another Beyond Pilot award winner this year is physician-scientist Kevin Cheung, MD, whose team is developing a monoclonal antibody drug to block necrosis, the formation of dead zones within a breast cancer tumor. An expert in breast cancer metastasis — the dissemination of tumor cells to other sites in the body — Cheung and others have shown that necrotic cores in breast tumors are sources of these spreading cells. His grant will explore his idea that necrosis, once thought an inevitable byproduct of aggressive cancer, might be preventable. His research project will screen for antibodies that can block a key protein secreted by tumor cells. His research shows that this protein promotes necrosis. The hope is that manufactured versions of the best protein-blocking antibodies could stop necrosis and therefore prevent metastasis, the leading cause of death for breast cancer patients.

Senior Staff Scientist Stefan Radtke, PhD, and colleagues will use their Beyond Pilot funding to develop further a suite of laboratory and clinical innovations that would help make possible “in vivo” gene therapies — where genetic changes are made inside the patient rather than in the lab — with the potential to cure HIV/AIDS and life-threatening blood disorders. In collaboration with transplantation scientist Hans-Peter Kiem, MD, PhD, holder of the Stephanus Family Endowed Chair for Cell and Gene Therapy, the team will focus on methods of delivering molecular-scale gene-editing tools specifically targeted to blood stem cells.

This gene therapy in-a-syringe would transform patients’ blood cells in their own bodies, bypassing the expensive process of removing cells and modifying them under cleanroom lab conditions before being reinfused. Cleanrooms and viral vectors — hollowed out viruses that carry the desired genes and editing molecules — are the major cost-drivers of gene therapy today. To address them, the team will test viruses engineered to home in on a subset of blood-forming stem cells called CD90s that are especially suited for rapid growth inside the body after modification.

Fred Hutch hematologist Roland Walter, MD, PhD, MS, and his team won a Beyond Pilot award for their project to develop a targeted radioimmunotherapy for adults with acute leukemia. Such therapeutics pair a tiny, radiation-emitting particle with an antibody that can home in on cancer cells. Their work has focused on a protein, CD123, seen on the surface of leukemic stem cells, but seldom on healthy cells. This precision targeting uses the radiation to kill the CD123-bearing cells, but not others. Having shown the therapy works in mice using a mouse antibody, the researchers are developing version using laboratory-made human antibodies attached to the radioactive particle. If pre-clinical tests with the new antibodies are successful, the researchers hope to interest drugmakers in developing versions suitable for human trials in patients with leukemia and other blood cancers that carry the CD123 target protein.

Four teams receive Pilot awards

Fred Hutch neurobiologist Aakanksha Singhvi, PhD, received a Pilot award for her project exploring a possible connection between Parkinson’s Disease and a brain cell maintenance process called “glial pruning.” In her work with the tiny roundworm C. elegans, Singhvi has shown that glial cells found in the brains of worms prune neuron fragments and other biological debris, presumably keeping our brains humming. Glial cells are also found in humans in numbers equal to the better-known neurons. Her project will explore whether defects in the inherited genes set off molecular processes that disrupt glial pruning. She will also test whether drugs that interfere with those flawed processes might restore proper pruning of brain cells, possibly reducing the damage diseases like Parkinson’s inflict on people.

Leukemia biology experts Soheil Meshinchi, MD, PhD, and Danielle Kirkey, MD, received a Pilot award for their team’s project to focus research on a recently discovered protein that might be a new target for therapeutics to treat acute myeloid leukemia. AML is a particularly lethal and aggressive form of leukemia with a survival rate of only 25-30%. Using extensive screening data from 3,000 patients, Meshinchi and collaborators discovered a novel target protein in a highly lethal type of AML associated with unique genetic alterations called KMT2A fusions. Kirkey will conduct studies to prove whether molecules tailored to bind to that protein, labeled CLEC2A, can knock out cancer cells that carry it. If that works, it could prompt development of T-cell therapeutics that home in and destroy cells that carry the target, providing hope for patients with this especially difficult-to-treat disease.

Graduate student Karthikeya Gottimukkala and gene therapy scientist Jennifer Adair, PhD, received Pilot funding for a project to develop a new generation of nanoparticles as vehicles for transporting molecular-scale gene-editing tools into human cells. Gottimukkala is a holder of the Curci Fellowship for International Graduate Students and Adair is a holder of the Fleischauer Family Endowed Chair in Gene Therapy Translation and a Fellow of the Uganda National Academy of Sciences. Their team will test a new type of gold nanoparticle that is simpler to assemble than previous designs. Gold nanoparticles are promising as replacements for viral vectors, whose slow production and high cost limit the growth potential of the gene therapy field. The new nanoparticles will be tried in a variety of human cell types to see if they outperform older versions. The new particles can be delivered without a boost of electricity, which is not suitable for syringe-delivered therapies that work inside the body. The particles will later be tested for safety and efficiency in mice.

Oncologist Irwin Bernstein, MD and staff scientist Suzanne Furuyama, PhD, are recipients of a Pilot award for a project to develop an inhibitor of DLK1, a gene that regulates stem cell growth and is associated with aggressive, chemotherapy-resistant cancers when it malfunctions. Overproduction of a protein made using the DLK1 gene is linked to myelodysplastic syndrome, or MDS, a form of cancer marked by improperly working blood cells that can transform into leukemia. Bernstein and Furuyama will screen for potent antibodies that can block DLK1 protein function on cell surfaces. Additionally, the researchers will search for protein variants or fragments that also can inhibit the suspected cancer-promoting molecular processes associated with DLK1 within cells. The goal is to advance the development of a drug that can treat MDS and other cancers linked to the gene.

Note: Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future.