Johnnie J. Orozco, MD, PhD, a Fred Hutch hematologist-oncologist and assistant program director for the fellowship program, developed a grant-writing seminar for applicants covering best practices for writing competitive research grant applications. Orozco stressed the importance of the mentorship aspect of Fred Hutch and UW’s Hematology-Oncology Fellowship Program in helping applicants to develop successful projects for the ASCO award.
“These awards are very impactful and really career-defining,” Orozco said. “We have many faculty members and trainees come to talk to the applicants. There’s a richness in that sort of mentorship that our applicants can really take advantage of, so that they can figure out how to strategize and put their best foot forward in the application process.”
Senior Vice President and Director of Fred Hutch’s Clinical Research Division Sara Hurvitz, MD, emphasized the importance of these early-career awards for Fred Hutch researchers.
“It’s a great honor to have five of our recent hematology-oncology fellows recognized by ASCO,” said Hurvitz, holder of the Smith Family Endowed Chair in Women’s Health. “The Young Investigator Award recognizes our fellows’ excellence and promise as future senior researchers, as well as the strength of our faculty mentors. We look forward to supporting the award recipients as they progress in their careers.”
Investigating climate’s impact in a rare fungal infection in leukemia
Climate change has important implications, particularly when it comes to the field of infectious disease. Fungi, for example, can adapt to warmer climates, leading to increased fungal infections in specific environments. During the first year of his fellowship, Kuczmarski cared for leukemia patients at UW Medical Center – Montlake.
In the clinic, he saw patients with severely compromised immune systems who were particularly susceptible to acquiring mucormycosis, a rare but serious fungal infection.
Working with his mentors, Steven Pergam, MD, MPH; Anna Halpern, MD; Jeremy Hess, MD, MPH; and statistician Elizabeth Krantz, Kuczmarski designed a research project to study whether conditions brought about by climate change might contribute to higher numbers of mucormycosis cases in leukemia patients. His project will examine historical data for patients treated at Fred Hutch to assess whether climate-related changes are correlated with increased infections.
“This is a potentially very good example of the health impacts of climate change,” said Kuczmarski.
Kuczmarski will examine all cases of mucormycosis infections diagnosed in patients treated at Fred Hutch over the last decade. He plans to examine climate data, such as precipitation levels, particulate matter in the air (associated with wildfire activity), and ambient temperature, to determine whether relationships exist between specific climate conditions and higher incidences of mucormycosis. This could lead to positive changes in infection control protocols for cancer patients in hospital settings and better health outcomes.
“By understanding the impact of climate patterns on these infections, we may be able to develop better strategies to prevent and treat this type of fungal infection in patients with blood cancers,” said Kuczmarski.
Could a drug for Parkinson’s disease treat leukemia?
Liu learned from her Fred Hutch mentor Derek L. Stirewalt, MD, that a specific protein was associated with an increased risk of developing Parkinson’s disease. Researchers have identified the same protein, LRRK2 (leucine-rich reverse kinase 2), in higher amounts in some patients with acute myeloid leukemia (AML), a particularly difficult form of leukemia to treat that is often seen in older adults.
Liu’s research project aims to learn whether a type of drug known as an LRRK2 inhibitor, currently in early phase clinical trials for treating Parkinson’s patients, could be used to treat AML patients whose cells express high levels of LRRK2. She developed her project with Stirewalt, with input from Fred Hutch scientists Soheil Meshinchi, MD, PhD, and Stanley Lee, PhD.
LRRK2 performs several functions in the cell, such as supporting cell signaling and protein-protein interactions. However, its role in AML is poorly understood. Liu suspects that the large amounts of LRRK2 found in some AML patients’ blood and bone marrow may play a role in allowing AML cells to survive and grow, potentially by influencing the process by which immune system cells differentiate into their various roles.
Liu will examine whether the LRRK2 inhibitor is also effective in killing AML cells with high levels of LRRK2. She will test her theories in both cell culture studies and mouse models. Liu hopes to collect enough data to support the development of a first-in-human clinical trial that could give new hope to AML patients with high levels of LRRK2.
“We know a lot about how leukemia cells are different than normal [blood] cells,” Liu said. “But we haven’t quite been able to make many major advances in terms of how we treat AML.”
While chemotherapy is still the standard therapy for most AML patients, the promise of targeted therapies such as the drug Liu will study in her ASCO project could provide a novel treatment for patients with specific cell targets in the future.
Combining two therapies for better CAR T-cell treatments for cancer
Huang devised a research project to determine whether two cancer therapies in combination could produce better outcomes for patients with chronic lymphocytic leukemia (CLL).
CLL is a slow-developing blood cancer that results in the overgrowth of a specific type of lymphocyte (an immune system cell located in the blood) known as a B cell. A type of protein known as Bruton’s tyrosine kinase, or BTK, becomes overactive in CLL patients. This leads to the growth of abnormal B cells.
A class of drugs known as BTK inhibitors has become a widely used therapy for CLL. Other CLL patients have been treated with chimeric antigen receptor-modified (CAR) T cells that have been engineered to intercept and destroy CLL cancer cells, but early results have shown there is much to improve upon. About 80% of CLL patients who undergo CAR T-cell treatment relapse and require other forms of treatment, according to the Lancet. Up to 30% of CLL patients experience significant side effects from CAR T-cell treatment as well.
Huang will work with Fred Hutch mentors Mazyar Shadman, MD, MPH; Jordan Gauthier, MD, MSc; and Lawrence Fong, MD, to investigate whether a combination of CAR T-cell therapy and BTK inhibitors helps strengthen CAR T cells so that they fight cancer cells more effectively. Shadman holds the Innovators Network Endowed Chair and Fong is the scientific director for Fred Hutch’s Immunotherapy Integrated Research Center (IIRC) and the Bezos Family Distinguished Scholar in Immunotherapy.
The project could lead to new types of combination therapies (combining more than one treatment known to work alone, but that could work more effectively together) for difficult-to-treat diseases such as CLL and other lymphomas.
“This will be the first in-depth study to look at how BTK inhibitors change how well CAR T cells work in patients,” Huang said. She hopes to eventually lead a clinical trial to determine whether this type of combination therapy is effective in patients.
Improving outcomes in the clinic
As a medical oncologist and researcher, Shih sees patients at several locations, including Fred Hutch’s South Lake Union Clinic and Harborview Medical Center. After witnessing firsthand how economic and other life challenges can keep cancer patients from accessing the care they need, she developed a project to identify potential improvements in various aspects of cancer care delivery to improve patient outcomes.
With mentors Scott Ramsey, MD, PhD, and Veena Shankaran, MD, the director and co-director, respectively, of the Hutchinson Institute for Cancer Outcomes Research (HICOR), Shih designed a project to identify opportunities for improving patient care by looking at the barriers that clinics and patients face in receiving targeted treatments for lung cancer.
Her research aims to identify challenges to receiving and affording patient care, as well as proposing initiatives that could ultimately address these challenges. Shih is particularly interested in increasing access to targeted therapies for cancers with specific genetic mutations after having a family member with lung cancer treated with this type of therapy. Her research will involve direct use of HICOR’s research resources, including existing databases and access to experts.
“Our cancer care system is just so complex,” she said. “The vast majority of people in health care would agree that it wasn’t designed in a patient-friendly manner. In the clinic, there is a lot of care coordination, and it can be very challenging to get your patients the therapies that we all agree they would benefit from. So [the ASCO project] is a nice opportunity to look at delivery and access to care, affordability of care and quality of care.”
Optimizing a drug target for prostate cancer cells
Prostate cancer is the second leading cause of cancer-related deaths in men, according to the Centers for Disease Control and Prevention. Raychaudhuri learned that a protein preferentially expressed on prostate cancer cell surfaces, PSMA (prostate-specific membrane antigen), can be targeted with a radiation-based drug known as Lutetium-177 Vipivotide Tetraxetan (or by the brand name Pluvicto). This drug works by binding to PSMA on cancer cells and delivering a lethal dose of radiation to that specific cell. These types of cellular therapies can reduce side effects typically associated with traditional chemotherapy.
However, not all prostate cancer patients express enough of the protein for the drug to work. Raychaudhuri’s research aims to learn whether a drug that can coax prostate cancer cells in mice into expressing PSMA works similarly in humans. If successful, this finding could lead to a new method for treating prostate cancer by helping the body to make more of a drug target to increase the effectiveness of cancer treatments such as Pluvicto.
Previous Fred Hutch research by pathologist Michael C. Haffner, MD, PhD, revealed that the DNA holding the instructions to make PSMA in some prostate cancer patients use a process called DNA methylation and acetylation to “hide” from the molecules that start the process of gene transcription and translation. This means that patients with this DNA modification make less of the PSMA molecule, inhibiting the ability of drugs like Pluvicto to target cancer cells with this marker.
“We found that patients with low PSMA levels store the DNA coding for PSMA in an abnormal way,” Raychaudhuri said. The drug vorinostat had previously been shown to increase PSMA levels in mouse studies. Raychaudhuri’s project, developed with Fred Hutch mentor Michael Schweizer, MD, aims to learn whether vorinostat has a similar effect in humans.
If successful in a clinical trial, this study could lead to Pluvicto being used together with vorinostat in prostate cancer patients with naturally lower levels of PSMA. Raychaudhuri’s hope is that this study will lead to improvements in the knowledge of PSMA, leading to new treatment approaches for prostate cancer.
