Siteman Investment Program Awards $2.44 Million for Cancer Research

Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine is pleased to announce funding for 13 new projects, including two clinical trials and community outreach and engagement efforts. Through this research, investigators aim to improve the understanding of tumor formation and growth, develop safer, more effective therapies, and remove barriers to precision medicine.

The funding is awarded through the Siteman Investment Program, which supports and accelerates the pace of innovation in cancer research. The money awarded comes from a variety of sources, including The Cancer Frontier Fund at The Foundation for Barnes-Jewish Hospital, which includes gifts from Pedal the Cause, the Foundation’s annual Illumination Gala, and donations throughout the year; the Cancer Center Support Grant (CCSG) from the National Cancer Institute; the Alvin J. Siteman Cancer Research Fund; Swim Across America – St. Louis; and various philanthropic gifts.

Please see below for more details about each funded project.

New Clinical Trial Category

Project Title: A Phase II, Single-Center, Open-Label Study of First-Line Ipilimumab plus Nivolumab and Nogapendekin Alfa Inbakicept (N-803) in Patients with Stage IV or Recurrent Non-Small Cell Lung Cancer (FLINN)

Principal Investigator: Giordano Cittolin Santos, MD, PhD
Co-PI: Daniel Morgensztern, MD

Goal: The study tests the hypothesis that adding nogapendekin alfa inbakicept (N-803), a drug that helps boost the immune system, to the already FDA-approved drug combination of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) will enhance anti-tumor responses in patients with stage IV or recurrent non-small cell lung cancer (NSCLC). Each drug activates the immune system through distinct but complementary mechanisms. Together, these agents may improve the depth and durability of clinical benefit compared with nivolumab and ipilimumab alone. In this study, patients will receive all three agents (nivolumab, ipilimumab, and N-803), and researchers will measure progression-free survival, overall clinical efficacy and the safety of this combination. They will also collect blood and tumor samples to understand how this treatment affects the immune system and the area around the tumor. The results of this study will clarify whether N-803 can further enhance the therapeutic effect of first-line immunotherapy and could establish a foundation for a future definitive trial aimed at improving outcomes for patients with advanced NSCLC.

Project Summary: Lung cancer is the leading cause of cancer-related death in the U.S., and most patients are diagnosed only after the disease has already spread and can no longer be cured with radiation or surgery. At this stage, the main goals of treatment are to relieve symptoms, slow cancer progression and help patients live longer. One of the most important advancements in lung cancer care has been the development of immunotherapy, a class of medications that help the body’s immune system recognize and attack cancer cells. Two immunotherapy drugs, nivolumab and ipilimumab, are already FDA-approved for first-line treatment of advanced non-small cell lung cancer (NSCLC). These medicines work by “releasing the brakes” on the immune system, allowing immune cells to attack the cancer more effectively. Although some patients achieve a long-lasting response to the immunotherapy combination, most either do not benefit or eventually experience cancer progression, highlighting the need for more effective and durable treatment options. Our study will test whether adding a new medicine called nogapendekin alfa inbakicept (N-803) can improve how well nivolumab and ipilimumab work in controlling lung cancer. N-803 acts like a natural protein that boosts the activity of two key immune cells: natural killer (NK) cells and CD8+ T cells. Earlier research has shown that combining N-803 with nivolumab is safe and may help control the cancer. N-803 is already FDA-approved for the treatment of early-stage bladder cancer. By giving all three medicines together, we hope to strengthen the immune system’s ability to fight lung cancer and achieve a more durable response. If successful, this study could lead to a new, more effective, chemotherapy-free treatment option for patients with advanced lung cancer and pave the way for a larger national study.

Project Title: A Double-Blind, Placebo-Controlled Phase lb Study Evaluating the Safety and Toxicity of Recombinant Human IL-7 (NT-I7) in Relapsed/Refractory Multiple Myeloma Following BCMA CAR-T Therapy (Cilta-cel)

Principal Investigator: Michael Slade, MD, MSCI

Goal: This is a two-arm, double-blind, placebo-controlled, randomized, phase Ib study testing the safety and toxicity of adding NT-I7 to BCMA CAR-T (standard of care) therapy in patients with relapsed/refractory multiple myeloma (RRMM). The hypothesis is that NT-I7 will help CAR T cells expand more and persist longer in the body, which will help get rid of multiple myeloma cells while still being safe. Patients receiving standard of care therapy will be randomized to either receive the addition of NT-I7 or a placebo. Correlative studies will evaluate CAR-T cell expansion, persistence, immune-phenotype, function and correlate with clinical outcomes.

Project Summary: Multiple myeloma is treated with medical therapy and stem cell transplant, but none of these therapies are curative. An alternate approach in myeloma therapy is to engineer patients’ own immune cells to detect and destroy myeloma cells. These chimeric antigen receptor T cell (or “CAR T cell”) therapies cause the cancer to shrink in 9 of 10 patients and can sometimes control myeloma for years, but are still not curative. Based on work in the researchers’ laboratory, the addition of a naturally occurring protein messenger called interleukin 7 (IL-7) can improve the ability of CAR T cells to get rid of blood cancer cells. In response to IL-7, CAR T cells divide more and persist longer, raising the possibility that the combination may be able to permanently eradicate myeloma cells. This study proposes the use of NT-I7, a long-acting version of IL-7, to improve myeloma-directed CAR T cell therapy. Similar drugs have been used to treat patients with severe infections and have been shown to be safe in that setting, with few side effects reported. By combining NT-I7 with standard-of-care CAR T cells, the researchers hope to enhance CAR T cell efficacy, achieve deeper remissions and achieve cures for patients with myeloma.

Pre-R01 Category

Project Title: Metabolic Control of Antigen Presentation in aCD40 Cancer Immunotherapy

Principal Investigator: Maxim Artyomov, PhD

Goal: To uncover how a chemical called itaconate affects the way our body recognizes and attacks harmful invaders called antigens. The researchers want to discover which antigens are most important for making our immune system respond strongly. By using advanced tools to study genes, metabolites and DNA, they will learn which immune cells are involved and how they can help the cells identify and destroy tumors more effectively.

Project Summary: This project explores how immunometabolic regulation within myeloid cells affects tumor antigen presentation and response to immunotherapy. The labs of Artyomov and Robert Schreiber, PhD, have long investigated mechanisms of tumor rejection, emphasizing the role of myeloid antigen-presenting cells. Their joint studies reveal that during effective immunotherapy, myeloid cells undergo a shift toward a pro-inflammatory and metabolically remodeled state — highlighting the metabolite itaconate as a key player in this transformation. Itaconate is produced in activated myeloid cells and has been shown to regulate immune responses. Preliminary data from the Artyomov lab show that mice deficient in itaconate (Irg1-/-) completely reject EG7 tumors when treated with αCD40 immunotherapy, while wild-type mice fail to do so. Mechanistically, itaconate inhibits GILT, a thiol reductase crucial for processing disulfide-rich neoantigens, thus impairing effective antigen presentation in wild-type settings. These findings support a novel hypothesis: Itaconate suppresses tumor antigen processing via GILT inhibition, thus limiting anti-tumor immunity. The significance and innovation of this proposal lie in several novel insights: (1) New Mechanistic Insight: It is the first to suggest that itaconate modulates cancer immunotherapy by directly impacting antigen processing through covalent modification of GILT and other endosomal proteases; (2) Complete Tumor Rejection Phenotype: Unlike previous studies focused on T cell–centered therapies like checkpoint inhibitors, αCD40 therapy in Irg1-/- mice results in complete tumor clearance, revealing the central role of myeloid metabolism in driving anti-tumor responses; and (3) Cutting-edge Tools and Expertise: The team possesses all required platforms — from in silico neoantigen prediction to in vivo validation — to dissect antigen presentation and immune responses.

Project Title: Defining and Targeting the Non-Transcriptional Functions of MYC in Acute Myeloid Leukemia

Principal Investigator: Francesca Ferraro, MD, PhD

Goal: To understand the different ways the MYC protein helps leukemia grow, both inside and outside the cell’s nucleus. By figuring out how MYC moves around the cell and controls RNA, the researchers hope to uncover new weaknesses in leukemia cells. Ultimately, this work aims to create safer and more effective treatment strategies for patients with acute myeloid leukemia (AML).

Project Summary: AML is one of the most aggressive blood cancers. Many patients relapse after treatment, and older adults often cannot tolerate intensive options like chemotherapy or bone marrow transplant. Because AML is driven by many different genetic changes, it has been very difficult to develop effective, targeted and less toxic treatments. One protein, called MYC, is abnormal in almost every case of AML and is a major driver of the disease. MYC normally works inside the nucleus of the cell to turn genes on and off. However, we still do not fully understand how MYC causes leukemia, especially because traditional drugs that try to block its gene-regulating role have not worked well in patients. Our recent research shows that MYC does more than control genes. We found that certain mutations in MYC can cause leukemia by changing where MYC is located inside the cell and by altering how it interacts with RNA. These effects happen outside the nucleus and represent a completely different way MYC may drive cancer. These discoveries suggest that MYC has additional, “extranuclear” functions that help leukemia grow, and that these functions could be targeted separately from MYC’s usual gene-regulating role. By revealing these new and unexpected roles of MYC, this research aims to lay the groundwork for more effective and less toxic treatments for AML and potentially other MYC-driven cancers

Project Title: The Role of Endogenous Memory NK Cells in Non-Small Cell Lung Cancer

Principal Investigator: Jennifer Foltz, PhD

Goal: To improve a type of immune cell called memory-like (ML) natural killer (NK) cells to help fight lung cancer. The researchers want to study these special immune cells in lung cancer patients to learn more about how they work. This understanding will give them the tools to develop better NK cell therapies for lung cancer. They will apply this knowledge to optimally design clinical trials that boost the patient’s own immune system to fight cancer.

Project Summary: Lung cancer is the leading cause of death from cancer. Recent therapies have been aimed at activating the patient’s immune system and have seen improved responses, but only a subset of patients have benefitted from this treatment. Therefore, new treatment options are needed. In this proposal, we are focused on natural killer (NK) cells, a type of immune cell that can kill cancer. We previously found that when we treat NK cells in the lab with three specific proteins, the NK cells develop memory, which means they are better at fighting cancer. For instance, lab-created memory NK cells have been shown to be effective at treating blood cancer. The researchers believe that memory NK cells could improve outcomes for solid tumor patients as well. They have found that memory NK cells were increased in lung cancer patients and that this increase remained even in lung cancer that has spread to the brain. However, researchers do not understand why memory NK cells, which are more effective at fighting blood cancer, are increased within lung cancer. This is the first study to identify that memory NK cells can reside in cancer without first creating them in the lab. This proposal will determine the ability of the endogenous — the body’s own — lung memory NK cells to fight off lung cancer. The researchers will measure the cells’ abundance. Also, they will measure the cells’ proximity to the tumor. Researchers will also identify how to can make the endogenous memory NK cells better at fighting cancer. These results are expected to provide critical data for longer-term funding. Working with collaborators, the researchers expect to develop a new clinical trial to activate endogenous memory NK cells in the future.

Project Title: A Novel Targeted Treatment Combination for BRAF Mutant Melanoma

Principal Investigator: Charles Kaufman, MD, PhD

Goal: To improve the effectiveness of current melanoma treatments to shrink tumors more and for a longer time. The researchers will test the combination of two FDA-approved drugs, dabrafenib and entrectinib, against human melanoma tumors previously isolated from patients and now grown in mice to mimic the natural behavior and growth environment of these tumors. This would establish a novel combination of FDA-approved drugs for melanoma that has a specific mutation (in a gene called BRAF) and no longer responds to current treatments. Success would support future clinical trials for this drug combination in humans.

Project Summary: Melanoma usually arises first on the skin and is extremely dangerous due to its tendency to spread, sometimes early, to other organs. Newly developed drugs have improved our ability to treat melanoma and prolong many patients’ lives. However, even our most quickly effective treatments, called targeted therapies, often work only for a limited time as melanoma eventually becomes resistant to these drugs and continues to grow and spread. For many patients, these targeted therapies are the last line of treatment that they can tolerate due to other medical issues or because of ongoing negative effects from prior treatments that overactivate the immune system. In this proposal, we seek to understand how melanoma becomes resistant to current targeted therapy and determine if we can overcome this resistance with other drug combinations. In our studies thus far, we have found an exciting new combination of existing and readily available drugs that may overcome this resistance in certain melanomas. This combination of two drugs works in resistant melanoma cells grown in the lab, and we now aim to test their effectiveness against human cells in mouse models. If successful, this study would provide essential support for future clinical trials for this drug combination in patients who have exhausted currently available treatments and who desperately need these additional treatment options for melanoma that would otherwise be nearly untreatable.

Project Title: Tumor-Associated Macrophage Modulated Radioimmunotherapy of Head and Neck Squamous Cell Carcinoma

Principal Investigator: Yongjian Liu, PhD

Goal: Head and neck squamous cell carcinoma (HNSCC) is a serious type of cancer that is hard to treat successfully. The area around the tumor (called the tumor microenvironment, or TME) can weaken the body’s immune response, making treatments less effective. To tackle this problem, the researchers have developed a new type of treatment that uses radiation to target certain immune cells called tumor-associated macrophages (TAMs). By doing this, they hope to change the TME so other treatments, like chemotherapy or immunotherapy, work better. The goal is to create a targeted radiation therapy that attacks specific TAMs called CD163+ to improve treatment for people with HNSCC.

Project Summary: Despite advances in prevention and treatment, survival for HNSCC patients has minimally improved over the past 30 years. The substantial morbidity and mortality rates for HNSCC and the toxicity associated with the standard treatment options emphasize the need to seek alternatives. Targeted radionuclide therapy (TRT) is a kind of treatment that delivers radiation directly to the cancer cells to minimize damage to healthy cells. This method has helped improve outcomes for some types of cancer. However, TRT can still cause problems over time, like treatment resistance and cancer coming back. So, the researchers need new ways to use TRT for treating HNSCC. Tumor-associated macrophages (TAMs), especially CD163+ TAMs, are an essential component of the tumor microenvironment and maintain a critical role in orchestrating tumor progression, metastasis and resistance to therapies. The goal of this application is to develop CD163+ TAM- targeted therapy for HNSCC. The researchers believe that using a special probe labeled with radioactive copper (64Cu/67Cu) can help them see and change the tumor environment, making other treatments like immunotherapy work better.

Project Title: Targeting COPS5 to Overcome PARP Inhibitor Resistance in Ovarian Cancer

Principal Investigator: Mary Mullen, MD, MSCI

Goal: To develop and test a new therapy for the most common type of ovarian cancer by targeting a protein called COPS5. Through rigorous mechanistic, translational, and preclinical studies, this work aims to establish COPS5 as a target for a new therapy that will weaken the tumor and make it more susceptible to other known treatments, such as PARP inhibitors.

Project Summary: Most patients with ovarian cancer develop resistance to standard treatments, including platinum chemotherapy and PARP inhibitors, resulting in a low five-year survival rate. Once resistance develops, there are limited effective treatment options. This research focuses on a protein called COPS5, which helps cancer cells repair DNA and survive therapy. Early results show that blocking COPS5 makes resistant ovarian cancer cells more sensitive to PARP inhibitors and increases treatment-related DNA damage. Patients with high COPS5 levels have worse outcomes. In this project, the researchers will determine whether COPS5 is elevated in tumors that do not respond to PARP inhibitors, test whether blocking COPS5 safely strengthens PARP inhibitor effectiveness, and study how COPS5 helps cancer cells resist therapy. This work will lay the foundation for developing new treatments that overcome resistance and help more women benefit from PARP inhibitors.

Project Title: Predicting Response of HER2-low Breast Tumors to Trastuzumab-Deruxtecan Through Quantitative Imaging

Principal Investigator: Patricia Ribeiro Pereira, PhD

Goal: The vast majority of patients with advanced breast cancer become resistant to anti-HER2 antibody-drug therapies. The use of predictive biomarkers (genes, proteins, or other molecules in the body) to guide antibody-drug response is necessary for improving survival in patients with breast cancer and for sparing them from unnecessary side effects. This proposal seeks to optimize a whole-body imaging approach that can identify how well Trastuzumab-drug conjugates will work against HER2-low breast tumors.

Project Summary: Breast cancer leads to a significant number of deaths each year. To reduce these numbers, we need effective ways to detect the disease and treat it. Antibody-drug conjugates, which are a combination of antibodies that specifically target cancer cells and a drug that kills them, have shown promise in treating breast tumors with high levels of a protein called HER2. Recently, some of these drugs have also been found to be effective in patients with tumors that have lower levels of HER2, but resistance occurs over time. In this proposal, the researchers will test approaches of whole-body imaging to identify which breast tumors will benefit most from antibody-drug therapies, reducing unnecessary side effects for those who may not respond well. In addition, the researchers will combine antibody drugs with other treatments to improve their efficacy. This approach will lead to future clinical trials that offer more effective options for diagnosing and treating breast cancer.

Project Title:Targeted Radionuclide Therapy for Cervical Cancer

Principal Investigator: Buck Rogers, PhD

Goal: To evaluate a new treatment for cervical cancer that uses a radioactive peptide that sticks to a specific protein (called integrin αvβ6) on the surface of tumor cells. If successful, this method will boost the effectiveness and safety of radiation treatment.

Project Summary: Cervical cancer is among the top cancers in incidence and mortality of young women worldwide, with about 350,000 cancer-related deaths per year. Following standard-of-care treatment, many locally advanced cervical cancer patients experience recurrence and have a five-year survival rate below 10%. Therefore, more sophisticated targeted therapeutic options are urgently needed to improve clinical outcomes. To address this, the researchers propose to deliver radiation in a specific manner to a protein that is highly expressed on cervical cancer cells but not on normal tissues. This protein is ideal for delivery of highly toxic radiation that can kill the cancer cells while not being toxic. The researchers have developed a novel peptide that carries radiation and, when injected into a living subject, will seek out this protein and bind strongly to it. In this proposal, the researchers will investigate the radioactive peptide for its binding properties to cervical cancer cells in a dish, followed by its evaluation in mice that have cervical cancer tumors. At the conclusion of these studies, the researchers anticipate they will have a well-characterized radioactive peptide that is ready to be moved into the clinic for the treatment of cervical cancer. In addition, this peptide can also be used for the treatment of other cancers, such as pancreatic, lung or breast cancer, since the protein it binds to is also highly expressed in these cancers.

Project Title: Imaging, Phenotyping, and Molecular Targeting of CD38-Resistant Multiple Myeloma Cells

Principal Investigator: Monica Shokeen, PhD, MBA

Goal: Multiple myeloma (MM) is an incurable blood cancer that nearly always relapses, and patients who fail CD38-targeted immunotherapies have poor survival measured in months. This project directly addresses an urgent clinical need by investigating mechanisms of resistance to CD38-targeted therapies. The findings of this proposal will ultimately guide development of new interventions to improve survival in patients with relapsed and refractory MM. The overall goal is to address the unmet clinical need to identify these aggressive and highly metastatic MM cells early on and identify effective treatments that will improve patient outcomes.

Project Summary: MM is the second most common blood cancer. It arises from abnormal plasma cells in the bone marrow that multiply uncontrollably and produce harmful levels of antibodies. This disease damages the bones, weakens the immune system, and can lead to kidney failure. Current treatments often work well at first, but nearly all patients eventually relapse with more aggressive disease, and no existing therapy can cure MM. A new class of drugs has targeted a protein called CD38, which is found in high amounts on most myeloma cells. Drugs such as daratumumab and isatuximab initially work well, but many patients either do not respond or become resistant, with survival dropping to less than six months once these treatments fail. Because CD38-targeted therapies are now being used earlier in treatment, resistance is expected to become even more common. Our research focuses on understanding why MM becomes more aggressive when CD38 is lost. In laboratory mouse models, myeloma cells without CD38 caused more bone damage, spread to the kidneys, and grew faster than normal myeloma cells. We also observed changes in several cellular pathways and abnormal blood chemistry, indicating that “CD38-low” myeloma is particularly dangerous. This project will study both the tumor cells themselves and the surrounding microenvironment to uncover how CD38 loss drives aggressiveness and resistance. By identifying the key pathways and markers of these high-risk cells, the researchers aim to develop strategies to detect them earlier and create more effective treatments. The long-term goal is to improve survival and quality of life for patients facing this incurable and often devastating disease.

Project Title: Identifying a DHX9 Pathway Vulnerability in Triple Negative Breast Cancer

Principal Investigator: Jason Weber, PhD

Goal: To define why triple negative breast cancer (TNBC) depends on the RNA helicase DHX9. The work will determine how TNBC cells use DHX9 to grow and survive. The project will test the DHX9 inhibitor ATX968 in TNBC models and measure its ability to slow growth and kill tumor cells. The results aim to provide the evidence needed to support a clinical trial in TNBC patients.

Project Summary: TNBC refers to breast cancers that lack estrogen, progesterone and HER2 receptors. This aggressive subtype of breast cancer is often metastatic and is associated with lower overall survival across all stages compared to other breast cancer subtypes. TNBC poses significant challenges to patients, clinicians and researchers due to a lack of effective therapies, its high mortality rate and the absence of a well-defined molecular target. Recent work points to a new opportunity. DHX9 is a protein that plays a crucial role in several important functions within cells, including how genes are turned on and off, and how genetic material is kept stable. Many cancers produce high levels of DHX9, and this pattern is linked to poorer outcomes. TNBC cells appear to rely on DHX9 to manage complex RNA structures that would otherwise trigger stress or cell death. This makes DHX9 a promising target for therapy. The researchers’ work shows that DHX9 is highly active in breast tumors with worse prognosis. The scientists reduced DHX9 in aggressive breast cancer cells and found that this led to slower growth and more cell death. These results suggest that TNBC cells depend on DHX9 to survive. Blocking the activity of the DHX9 protein may also help the immune system recognize and attack these tumors. This project will build on these findings using tissue samples from patients and mouse models of TNBC. The researchers will use a new drug called ATX968 that inhibits DHX9 activity and has already been cleared for initial testing in humans.

COE Supplement

Project Title: Leveraging Community Input for AI-based Applications for Cancer Patients and Caregivers

Principal Investigator: Jacqueline Payton, MD, PhD
Project Leads: Felicia Gomez, PhD, and Erin Linnenbringer, PhD, MS

Goal: To define the unique factors that impact molecular cancer testing and outcomes in patients throughout the Siteman catchment area. The researchers aim to deliver community-informed, AI based methods to compare access to precision medicine and its impact on cancer outcomes. They further expect to develop a prototype AI-based application for interactive use by community patients and caregivers to address barriers to molecular testing and precision medicine therapies.

Project Summary: In this pilot study, the researchers will leverage large language models (LLM), a type of artificial intelligence designed to standardize and accelerate the review of bulk data, to collate cancer molecular testing data, social determinants of health (SDOH) and cancer-specific outcomes from notes extracted from medical records. LLM-extracted data will be compared to manually abstracted data performed by an oncology clinical coordinator from the same patient charts.

In parallel, the researchers will seek input and feedback from their community partner, the Cancer Support Community of Greater St. Louis. Through that network, the researchers will engage participants to understand their knowledge of precision medicine, the barriers they have faced and their thoughts on artificial intelligence.

The researchers will incorporate their input into a prototype AI-based application and elicit additional feedback via testing of the improved prototype.